Imidazole and imidazoline derivatives and uses thereof

ABSTRACT

This invention is directed to novel imidazole and imidazoline derivatives which are selective agonists for cloned human α 2  adrenergic receptors. This invention is also related to the use of these compounds for the treatment of any disease where modulation of the α 2  receptors may be useful. The invention further provides for a pharmaceutical composition comprising a therapeutically effective amount of the above-defined compounds and a pharmaceutically acceptable carrier.

This application is a continuation of U.S. Ser. No. 09/398,861, filedSep. 20, 1999, now U.S. Pat. No. 6,294,566, a continuation of U.S. Ser.No. 09/175,253, filed Oct. 20, 1998, now U.S. Pat. No. 6,093,727, issuedJul. 25, 2000, and a divisional of U.S. Ser. No. 08/834,658, filed Apr.11, 1997, now U.S. Pat. No. 5,866,579, issued Feb. 2, 1999, the contentsof which are hereby incorporated by reference into the subjectapplication.

BACKGROUND OF THE INVENTION

Throughout this application, various references are referred to withinparentheses. Disclosure of these publications in their entireties arehereby incorporated by reference into this application to more fullydescribe the state of the art to which this invention pertains.

α-Adrenergic receptors (Lomasney, J. W. et al., Biochim. Biophy. Acta1991, 1095, 127) are cell membrane proteins located in both theperipheral and central nervous systems. They belong to a diverse familyof structurally related receptors which contain seven putativetransmembrane helices and couple to intracellular guanine nucleotidebinding proteins (G-proteins). These receptors are important switchesfor controlling many physiological functions and, thus, representimportant targets for drug development. In fact, many α-adrenergic drugshave been developed over the past 40 years. Examples include clonidine,phenoxybenzamine and prazosin (for treatment of hypertension),naphazoline (for nasal decongestion), medetomidine (for veterinaryanalgesia), UK-14,304 and apraclonidine (for glaucoma). α-Adrenergicdrugs can be divided into two distinct classes: agonists (like clonidineand naphazoline) which mimic the receptor activation properties of theendogenous neurotransmitter norepinephrine, and antagonists (likephenoxybenzamine and prazosin) which act to block the effects ofnorepinephrine. However, many of these drugs, though effective, alsoproduce undesirable side effects. For example, clonidine produces drymouth and sedation in addition to its antihypertensive effects.

Prior to 1977, only one α-adrenergic receptor was known to exist.Between 1977 and 1988, it was accepted by the scientific community thatat least two α-adrenergic receptors α₁ and α₂ existed. Since 1988, newtechniques in molecular biology have led to the identification of atleast six α-adrenergic receptors—α_(1a), α_(1b), α_(1c), α_(2a), α_(2b)and α_(2c) (Bylund, D. B., FASEB J. 1992, 6, 832). In addition, currentα₂-adrenergic drugs are not selective for any particular α₂-adrenergicreceptor subtype. This lack of selectivity likely contributes to theuntoward side effects of these drugs.

α₂ receptors are located both presynaptically at nerve terminals andpostsynaptically as in vascular smooth muscles, platelets, pancreaticβ-cells, and fat cells. Activation of the presynaptic receptors inhibitthe release of norepinephrine by a negative feedback mechanism. Blockadeof these receptors would therefore increase the release ofnorepinephrine.

It is believed that α₂ receptors can modulate pain. Indeed, the effectsof α₂ agonists on analgesia, anesthesia and sedation have been welldocumented (Pertovaara, A., Progress in Neurobiology, 1993, 40, 691).For example, systemic administration of clonidine has been shown toproduce antinociception in various species including human patients inaddition to its well known sedative effects. Intrathecal and epiduraladministration of clonidine has also proves effective in producinganalgesia. Another agonist, medetomidine, which has better α₂/α₁selectivity and is more potent at α₂ receptors than clonidine, has beenshown in humans to be effective for ischemic pain even though the doseswere high enough to produce sedation and considerable decrease in bloodpressure.

However, in anesthetic practice, the sedative effect of α₂ agonists isregarded as a good component of premedication.

Another beneficial effect of α₂ agonists is their ability to potentiatethe anesthetic action and hence to reduce the anesthetic requirements ofother agents during surgery (Ghingnone, M. et al., Anesthesiology 1986,64, 36).

Other potential uses of α₂ agonists include lowering intraocularpressure, treating hypertension, alcohol and drug withdrawal, rheumatoidarthritis, ischemia, migraine, cognitive deficiency, spasticity,diarrhea and nasal congestion (Cossement, E. et al., U.S. Pat. No.4,923,865, 1990).

This invention is directed to imidazole and imidazoline compounds whichare selective agonists for human α₂ receptors. This invention is alsorelated to the use of these compounds for treating disorders involvinginhibition or lack of activation of α₂ adrenergic receptors such ashypertension, pain, glaucoma, alcohol and drug withdrawal, rheumatoidarthritis, ischemia, migraine, cognitive deficiency, spasticity,diarrhea and nasal congestion.

SUMMARY OF THE INVENTION

This invention is directed to imidazole and imidazoline compounds whichare selective agonists for human α₂ receptors. This invention is alsorelated to the use of these compounds for treating disorders involvinginhibition or lack of activation of a adrenergic receptors such ashypertension, pain, glaucoma, alcohol and drug withdrawal, rheumatoidarthritis, ischemia, migraine, cognitive deficiency, spasticity,diarrhea and nasal congestion. The invention further provides apharmaceutical composition comprising a therapeutically effective amountof the above-defined compounds and a pharmaceutically acceptablecarrier.

The present invention provides a compound having the structure:

wherein X is CR₇; N; or N⁺O⁻;

wherein Y is O; CO; S; CR₃R₅; or NR₆;

wherein each R₂ is independently H; F; Cl; Br; I; —NO₂, —CN; straightchained or branched C₁-C₄ alkyl; C₁-C₄ monofluoroalkyl or C₁-C₄polyfluoroalkyl; straight chained or branched C₁-C₄ alkoxy; —OH;—(CH₂)₃OH; —COR₄; CO₂R₄; CONHR₄; phenyl; or benzyl;

wherein each R₃ is independently H; straight chained or branched C₁-C₄alkyl; C₁-C₄ monofluoroalkyl or C₁-C₄ polyfluoroalkyl; straight chainedor branched C₁-C₄ alkoxy; —(CH₂)_(q)OH; —OH; ═N—OR₄; COR₄; CO₂R₄;CONHR₄; phenyl; or benzyl;

wherein each R₄ is independently H; straight chained or branched C₁-C₄alkyl, C₁-C₄ monofluoroalkyl or C₁-C₄ polyfluoroalkyl; or phenyl;

wherein each R₅ is independently H; straight chained or branched C₁-C₄alkyl, C₁-C₄ monofluoroalkyl, or C₁-C₄ polyfluoroalkyl;

wherein R₆ is H; straight chained or branched C₁-C₄ alkyl; C₁-C₄monofluoroalkyl or C₁-C₄ polyfluoroalkyl; straight chained or branchedC₁-C₄ alkoxy; —CH₂CH₂(CH₂)_(q)OH; COR₄; CO₂R₄; CONHR₄; phenyl; orbenzyl;

wherein each R₇ is independently H; —CN; straight chained or branchedC₁-C₄ alkyl; C₁-C₄ monofluoroalkyl or C₁-C₄ polyfluoroalkyl; straightchained or branched C₁-C₄ alkoxy; —OH; —(CH₂)_(q)OH; —COR₄; CO₂R₄;CONHR₄; phenyl; or benzyl;

wherein m and n are each independently 0, 1, 2 or 3, provided that m+nis 2 or 3;

wherein each p is independently 0, 1 or 2; and

wherein each q is independently 0, 1, 2 or 3;

or a pharmaceutically acceptable salt thereof.

The present invention also provides a compound having the structure:

wherein each of Z1, Z2 and Z3 is N or CR₂, with the proviso that eitherone of Z1, Z2 or Z3 is N and the others of Z1, Z2 or Z3 are CR₂, or bothZ1 and Z3 are N and Z2 is CR₂;

wherein R₁ is H; F; straight chained or branched C₁-C₄ alkyl, C₁-C₄monofluoroalkyl or C₁-C₄ polyfluoroalkyl; straight chained or branchedC₁-C₄ alkoxy, —OH; or —(CH₂)_(q)OH;

wherein each R₂ is independently H; F; Cl; Br; I; —NO₂, —CN; straightchained or branched C₁-C₄ alkyl; C₁-C₄ monofluoroalkyl or C₁-C₄polyfluoroalkyl; straight chained or branched C₁-C₄ alkoxy; —OH;—(CH₂)_(q)OH; —COR₄; COR₂R₄; CONHR₄; phenyl; or benzyl;

wherein each R₄ is independently H; straight chained or branched C₁-C₄alkyl, C₁-C₄ monofluoroalkyl or C₁-C₄ polyfluoroalkyl; or phenyl; and

wherein q is each independently 0, 1, 2 or 3;

or a pharmaceutically acceptable salt thereof.

The present invention also provides a pharmaceutical compositioncomprising a therapeutically effective amount of the compounds describedherein and a pharmaceutically acceptable carrier.

The present invention further provides a method for treating an α₂adrenergic receptor associated disorder in a subject, which comprisesadministering to the subject an amount of a compound effective to treatthe disorder, wherein the compound has the structure:

wherein X is CR₇; N; or N⁺O⁻;

wherein Y is O; CO; S; CR₃R₅; or NR₆;

wherein each R₂ is independently H; F; Cl; Br; I; —NO₂, —CN; straightchained or branched C₁-C₄ alkyl; C₁-C₄ monofluoroalkyl or C₁-C₄;polyfluoroalkyl; straight chained or branched C₁-C₄ alkoxy; —OH;—(CH₁)_(q)OH; —COR₄; CO₂R₄; CONHR₄; phenyl; or benzyl;

wherein each R₂ is independently H; straight chained or branched C₁-C₄alkyl; C₁-C₄ monofluoroalkyl or C₁-C₄ polyfluoroalkyl; straight chainedor branched C₁-C₄ alkoxy; —(CH₂)_(q)OH; —OH; ═N—OR₄; COR₄; COR₄; CONHR₄;phenyl; or benzyl;

wherein each R₄ is independently H; straight chained or branched C₁-C₄alkyl, C₁-C₄ monofluoroalkyl or C₁-C₄ polyfluoroalkyl; or phenyl;

wherein each R₅ is independently H; straight chained or branched C₁-C₄alkyl, C₁-C₄ monofluoroalkyl, or C₁-C₄ polyfluoroalkyl;

wherein R₆ is H; straight chained or branched C₁-C₄ alkyl; C₁-C₄monofluoroalkyl or C₁-C₄ polyfluoroalkyl; straight chained or branchedC₁-C₄ alkoxy; —CH₂CH₂(CH₂)_(q)OH; COR₄; CO₂R₄; CONHR₄; phenyl; orbenzyl;

wherein each R₇ is independently H; —CN; straight chained or branchedC₁-C₄ alkyl; C₁-C₄ monofluoroalkyl or C₁-C₄ polyfluoroalkyl; straightchained or branched C₁-C₄ alkoxy; —OH; —(CH₂)_(q)OH; —COR₄; CO₂R₄;CONHR₄; phenyl; or benzyl;

wherein m and n are each independently 0, 1, 2 or 3, provided that m+nis 2 or 3;

wherein each p is independently 0, 1 or 2; and

wherein each q is independently 0, 1, 2 or 3;

or a pharmaceutically acceptable salt thereof.

The present invention additionally provides a method for treating an α₂adrenergic receptor associated disorder in a subject, which comprisesadministering to the subject an amount of a compound effective to treatthe disorder, wherein the compound has the structure:

wherein each of Z1, Z2 and Z3 is N or CR₂, with the proviso that eitherone of Z1, Z2 or Z3 is N and the others of Z1, Z2 or Z3 are CR₂, or bothZ1 and Z3 are N and Z2 is CR₂;

wherein R₁ is H; F; straight chained or branched C₁-C₄ alkyl, C₁-C₄monofluoroalkyl or C₁-C₄ polyfluoroalkyl; straight chained or branchedC₁-C₄ alkoxy, —OH; or —(CH₂)_(q)OH;

wherein each R₂ is independently H; F; Cl; Br; I; —NO₂, —CN; straightchained or branched C₁-C₄ alkyl; C₁-C₄ monofluoroalkyl or C₁-C₄polyfluoroalkyl; straight chained or branched C₁-C₄ alkoxy; —OH;—(CH₂)_(q)OH; —COR₄; CO₂R₄; CONHR₄; phenyl; or benzyl;

wherein each R₄ is independently H; straight chained or branched C₁-C₄alkyl, C₁-C₄ monofluoroalkyl or C₁-C₄ polyfluoroalkyl; or phenyl; and

wherein q is each independently 0, 1, 2 or 3;

or a pharmaceutically acceptable salt thereof.

The present invention also provides a method for treating pain in asubject, which comprises administering to the subject an amount of acompound effective to treat the subject's pain, wherein the compound hasthe structure:

wherein X is CR₇; N; or N⁺O⁻;

wherein Y is O; CO; S; CR₃R₅; or NR₆;

wherein each R₂ is independently H; F; Cl; Br; I; —NO₂, —CN; straightchained or branched C₁-C₄ alkyl; C₁-C₄ monofluoroalkyl or C₁-C₄polyfluoroalkyl; straight chained or branched C₁-C₄ alkoxy; —OH;—(CH₂)_(q)OH; —COR₄; CO₂R₄; CONHR₄; phenyl; or benzyl;

wherein each R₃ is independently H; straight chained or branched C₁-C₄alkyl; C₁-C₄, monofluoroalkyl or C₁-C₄ polyfluoroalkyl; straight chainedor branched C₁-C₄ alkoxy; —(CH₂)_(q)OH; —OH; ═N—OR₄; COR₄; CO₂R₄;CONHR₄; phenyl; or benzyl;

wherein each R₄ is independently H; straight chained or branched C₁-C₄alkyl, C₁-C₄ monofluoroalkyl or C₁-C₄ polyfluoroalkyl; or phenyl;

wherein each R₅ is independently H; straight chained or branched C₁-C₄alkyl, C₁-C₄ monofluoroalkyl, or C₁-C₄ polyfluoroalkyl;

wherein R₆ is H; straight chained or branched C₁-C₄ alkyl; C₁-C₄monofluoroalkyl or C₁-C₄ polyfluoroalkyl; straight chained or branchedC₁-C₄ alkoxy; —CH₂CH₂(CH₂)_(q)OH; COR₄; CO₂R₄; CONHR₄; phenyl; orbenzyl;

wherein each R₇ is independently H; —CN; straight chained or branchedC₁-C₄ alkyl; C₁-C₄ monofluoroalkyl or C₁-C₄ polyfluoroalkyl; straightchained or branched C₁-C₄ alkoxy; —OH; (CH₂)_(q)OH; —COR₄; CO₂R₄;CONHR₄; phenyl; or benzyl;

wherein m and n are each independently 0, 1, 2 or 3, provided that m+nis 2 or 3;

wherein each p is independently 0, 1 or 2; and

wherein each q is independently 0, 1, 2 or 3;

or a pharmaceutically acceptable salt thereof.

The present invention provides a method for treating pain in a subject,which comprises administering to the subject an amount of a compoundeffective to treat the subject's pain, wherein the compound has thestructure:

wherein each of Z1, Z2 and Z3 is N or CR₂, with the proviso that eitherone of Z1, Z2 or Z3 is N and the others of Z1, Z2 or Z3 are CR₂, or bothZ1 and Z3 are N and Z2 is CR₂;

wherein R₁ is H; F; straight chained or branched C₁-C₄ alkyl, C₁-C₄monofluoroalkyl or C₁-C₄ polyfluoroalkyl; straight chained or branchedC₁-C₄ alkoxy, —OH; or —(CH₂)_(q)OH;

wherein each R₂ is independently H; F; Cl; Br; I; —NO₂, —CN; straightchained or branched C₁-C₄ alkyl; C₁-C₄ monofluoroalkyl or C₁-C₄polyfluoroalkyl; straight chained or branched C₁-C₄ alkoxy; —OH;—(CH₂)_(q)OH; —COR₄; CO₂R₄; CONHR₄; phenyl; or benzyl;

wherein each R₄ is independently H; straight chained or branched C₁-C₄alkyl, C₁-C₄ monofluoroalkyl or C₁-C₄ polyfluoroalkyl; or phenyl; and

wherein q is each independently 0, 1, 2 or 3;

or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds having the structure:

wherein X is CR₇; N; or N⁺O⁻;

wherein Y is O; CO; S; CR₃R₅; or NR₆;

wherein each R₂ is independently H; F; Cl; Br; I; —NCO, —CN; straightchained or branched C₁-C₄ alkyl; C₁-C₄ monofluoroalkyl or C₁-C₄polyfluoroalkyl; straight chained or branched C₁-C₄ alkoxy; —OH;—(CH₂)_(q)OH; —COR₄; CO₂R₄; CONHR₄; phenyl; or benzyl;

wherein each R₃ is independently H; straight chained or branched C₁-C₄alkyl; C₁-C₄ monofluoroalkyl or C₁-C₄ polyfluoroalkyl; straight chainedor branched C₁-C₄ alkoxy; —(CH₂)_(q)OH; —OH; ═N—OR₄; COR₄; CO₂R₄;CONHR₄; phenyl; or benzyl;

wherein each R₄ is independently H; straight chained or branched C₁-C₄alkyl, C₁-C₄; monofluoroalkyl or C₁-C₄ polyfluoroalkyl; or phenyl;

wherein each R₅ is independently H; straight chained or branched C₁-C₄alkyl, C₁-C₄ monofluoroalkyl, or C₁-C₄ polyfluoroalkyl;

wherein R₆ is H; straight chained or branched C₁-C₄ alkyl; C₁-C₄monofluoroalkyl or C₁-C₄ polyfluoroalkyl; straight chained or branchedC₁-C₄ alkoxy; —CH₂CH₂(CH₂)_(q)OH; COR₄; CO₂R₄; CONHR₄; phenyl; orbenzyl;

wherein each R₇ is independently H; —CN; straight chained or branchedC₁-C₄ alkyl; C₁-C₄ monofluoroalkyl or C₁-C₄ polyfluoroalkyl; straightchained or branched C₁-C₄ alkoxy; —OH; —(CH₂)_(q)OH; —COR₄; CO₂R₄;CONHR₄; phenyl; or benzyl;

wherein m and n are each independently 0, 1, 2 or 3, provided that m+nis 2 or 3;

wherein each p is independently 0, 1 or 2; and

wherein each q is independently 0, 1, 2 or 3;

or a pharmaceutically acceptable salt thereof.

The present invention is also directed to compounds having thestructure:

wherein each of Z1, Z2 and Z3 is N or CR₂, with the proviso that eitherone of Z1, Z2 or Z3 is N and the others of Z1, Z2 or Z3 are CR₂, or bothZ1 and Z3 are N and Z2 is CR₂;

wherein R₁ is H; F; straight chained or branched C₁-C₄ alkyl, C₁-C₄monofluoroalkyl or C₁-C₄ polyfluoroalkyl; straight chained or branchedC₁-C₄ alkoxy, —OH; or —(CH₂)_(q)OH;

wherein each R₂ is independently H; F; Cl; Br; I; —NO, —CN; straightchained or branched C₁-C₄ alkyl; C₁-C₄ monofluoroalkyl or C₁-C₄polyfluoroalkyl; straight chained or branched C₁-C₄ alkoxy; —OH;—(CH₂)_(q)OH; —COR₄; CO₂R₄; CONHR₄; phenyl; or benzyl;

wherein each R₄ is independently H; straight chained or branched C₁-C₄alkyl, C₁-C₄ monofluoroalkyl or C₁-C₄ polyfluoroalkyl; or phenyl; and

wherein a is each independently C, 1, 2 or 3;

or a pharmaceutically acceptable salt thereof.

Furthermore, the compounds of the present invention are preferably atleast 80% pure, more preferably at least 90% pure, and most preferablyat least 95% pure. The invention further provides for the (+) or (−)enantiomer of any of the compounds described herein such as a cis isomeror trans isomer.

The compounds of the present invention may be present as enantiomers,disteriomers or isomers, or as a racemic mixture.

The present invention also includes tautomeric forms of compounds I;e.g., when X is N and R2 on the adjacent carbon atom is —OH, R2 maytautomerize with X to form a ketone at R2.

The present invention also encompasses compounds wherein two R₃s ondifferent carbon atoms form a bridging methylene or ethylene.

In an embodiment of the present invention Y is CR₃R₅, and m+n is 3. In afurther embodiment of the present invention Y is CR₃R₅ and m+n is 2.

In a further embodiment of the present invention Y is NR₆. In anotherembodiment of the present invention X is N.

In an additional embodiment of the present invention two of Z1, Z2 andZ3 are CR₂ and the other is N.

In an embodiment of the present invention p is at least 1 and at leastone R₃ is methyl. In a further embodiment of the present invention p isat least 1, at least one R₃ is methyl and X is N.

In another embodiment of the present invention at least one R₂ ismethyl. In a further embodiment of the present invention R₂ is methyland X is N.

In yet another embodiment of the present invention at least one R₂ isbromo. In a further embodiment of the present invention at least one R,is bromo and X is N.

In an additional embodiment of the present invention at least one R₂ ismethyl or phenyl. In yet another embodiment of the present invention R₁is C₁-C₃ alkyl, C₁-C₃ alkoxy, or —OH.

In an embodiment of the present invention the compound has thestructure:

In a further embodiment of the present invention the compound has thestructure:

In an additional embodiment of the present invention the compound hasthe structure:

In a further embodiment of the present invention the compound has thestructure:

In an embodiment of the present invention the compound has thestructure:

The present invention also provides a pharmaceutical compositioncomprising a therapeutically effective amount of the compounds describedherein and a pharmaceutically acceptable carrier. In the presentinvention a “therapeutically effective amount” is any amount of acompound which, when administered to a subject suffering from a disorderagainst which the compound is effective, causes reduction, remission orregression of the disorder. In one embodiment, the therapeuticallyeffective amount is an amount from about 0.01 mg per subject per day toabout 500 mg per subject per day, preferably from about 0.1 mg persubject per day to about 60 mg per subject per day, and most preferablyfrom about 1 mg per subject per day to about 20 mg per subject per day.In the practice of this invention, the “pharmaceutically acceptablecarrier” is any physiological carrier known to those of ordinary skillin the art useful in formulating pharmaceutical compositions.

The invention includes the pharmaceutically acceptable salts andcomplexes of all the compounds described herein. The salts include butare not limited to the following acids and bases. Examples of suitableinorganic acids include, but are not limited to, hydrochloric acid,hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid andboric acid. Examples of suitable organic acids include but are notlimited to acetic acid, trifluoroacetic acid, formic acid, oxalic acid,malonic acid, succinic acid, tartaric acid, maleic acid, fumaric acid,oxalic acid, methanesulfonic acid, trifluoromethanesulfonic acid,benzoic acid, glycolic acid, lactic acid, citric acid and mandelic acid.Examples of suitable inorganic bases include, but are not limited to,ammonia, hydroxyethylamine and hydrazine. Examples of suitable organicbases include, but are not limited to, methylamine, ethylamine, trimethyamine, trethylamine, ethylenediamine, hydroxyethylamine, morpholine,piperazine and guanidine. The invention further provides for thehydrates and polymorphs of all of the compounds described herein.

In one preferred embodiment, the pharmaceutical carrier may be a liquidand the pharmaceutical composition would be in the form of a solution.In another equally preferred embodiment, the pharmaceutically acceptablecarrier is a solid and the pharmaceutical composition is in the form ofa powder of tablet. In a further embodiment, the pharmaceutical carrieris a gel and the pharmaceutical composition is in the form of asuppository or cream. In a further embodiment, the compound may beformulated as part of a pharmaceutically acceptable transdermal patch.

A solid carrier can include one or more substances which may also act asflavoring agents, lubricants, solubilizers, suspending agents, fillers,glidants, compression aids, binders or tablet-disintegrating agents; itcan also be an encapsulating material. In powders, the carrier is afinely divided solid which is in admixture with the finely dividedactive ingredient. In tablets, the active ingredient is mixed with acarrier having the necessary compression properties in suitableproportions and compacted in the shape and size desired. The powders andtablets preferably contain up to 99% of the active ingredient. Suitablesolid carriers include, for examples, calcium phosphate, magnesiumstearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose,polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Liquid carriers are used in preparing solutions, suspensions, emulsions,syrups, elixirs and pressurized compositions. The active ingredient canbe dissolved or suspended in a pharmaceutically acceptable liquidcarrier such as water, an organic solvent, a mixture of both, orpharmaceutically acceptable oils or fats. The liquid carrier can containother suitable pharmaceutical additives such as solubillzers,emilsifiers, buffers, preservatives, sweeteners, flavoring agents,suspending agents, thickening agents, colors, viscosity regulators,stabilizers or osmo-regulators. Suitable examples of liquid carriers fororal and parenteral administration include water (partially containingadditives as above, e.g. cellulose derivatives, preferably sodiumcarboxymethyl cellulose solution), alcohols (including monohydric andpolyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g.fractionated coconut oil and arachis oil). For parenteraladministration, the carrier can also be an oily ester such as ethyloleate and isopropyl myristate. Sterile liquid carriers are useful insterile liquid form compositions for parenteral administration. Theliquid carrier for pressurized compositions can be halogenatedhydrocarbon or other pharmaceutically acceptable propellant, which areuseful for intranasal administration.

Liquid pharmaceutical compositions which are sterile solutions orsuspensions can be utilized for intramuscular, intrathecal,intratracheal, epidural, intraperitoneal or subcutaneous injections.Sterile solutions can also be administered intravenously. The compoundsmay be prepared as a sterile solid composition which may be dissolved orsuspended at the time of administration using sterile water, saline, orother appropriate sterile injectable medium. Carriers are intended toinclude necessary and inert binders, suspending agents, lubricants,flavorants, sweeteners, preservatives, dyes and coatings.

The compound can be administered orally in the form of a sterilesolution or suspension containing other solutes or suspending agents,for example, enough saline or glucose to make the solution isotonic,bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleateesters of sorbitol and its anhydrides copolymerized with ethylene oxide)and the like.

The compound can also be administered orally either in liquid or solidcomposition form. Compositions suitable for oral administration includesolid forms such as pills, capsules, granules, tablets and powders, andliquid forms such as solutions, syrups, elixirs and suspensions. Formsuseful for parenteral administration include sterile solutions,emulsions and suspensions.

Examples of suitable pharmaceutical carriers include any of the standardpharmaceutically accepted carriers known to those of ordinary skill inthe art. Examples of such pharmaceutical carriers include, but are notlimited to, phosphate buffered saline solution, water, emulsions such asoil/water emulsions or a triglyceride emulsion, various types of wettingagents, tablets, coated tablets and capsules. A suitablepharmaceutically acceptable carrier may be selected taking into accountthe chosen mode of administration.

Besides containing an effective amount of the compounds described hereinthe pharmaceutical compositions may also include suitable diluents,preservatives, solubilizers, emulsifiers, adjuvant and/or carriers.

The resulting pharmaceutical compositions may be liquids or lyophilizedor otherwise dried formulations. Examples of suitable diluents include,but are not limited to, Tris-HCL, Tris-acetate and Tris-phosphate. Thediluents employed may vary in their buffer content, pH and/or ionicstrength. Examples of representative additives which may be used in thepresent invention include, but are not limited to, albumin or gelatin toprevent absorption to surfaces, detergents (e.g., Tween 20, Tween 80,Pluronic F68, bile acid salts), solubilizing agents (e.g., Thimerosal,benzyalcohol), bulking substances or tonicity modifiers (e.g., lactose,mannitol), covalent attachment of polymers such as polyethylene glycolto the protein, complexation with metal ions, or incorporation of thematerial into or onto particulate preparation of polymeric compoundssuch as polylactic acid, polyglycolic acid, polyvinyl pyrrolidone, etc.or into liposomes, microemulsions, micelles, unilamellar or multimellarvesicles, erythrocyte ghosts, or spheroplasts. Such compositions willinfluence the physical state, solubility, stability, rate of in vivorelease, and rate of in vivo clearance of the compounds.

Examples of optional ingredients which may be included in thepharmaceutical compositions of the present invention includeantioxidants, e.g., ascorbic acid; low molecular weight (less than aboutten residues) polypeptides, i.e., polyarginine or tripeptide; proteins,such as serum albumin, gelatin, or immunoglobulins; amino acids, such asglycine, glutamine acid, aspartic acid, or arginine; chelating agentssuch as EDTA; and sugar alcohols such as mannitol or sorbitol.

The choice of composition will depend on the physical and chemicalproperties of the compounds. Controlled or sustained releasecompositions include formulation of lipophilic depots (e.g., fattyacids, waxes, oils). Also comprehended by the invention are particulatecompositions coated with polymers (e.g., poloxamers or poloxamines) andcompounds coupled to antibodies directed against tissue-specificreceptors, ligands or antigens or coupled to ligands of tissue-specificreceptors. Other embodiments of the compositions of the inventionincorporate particulate forms protective coatings, protease inhibitorsor permeation enhancers for various routes of administration, includingparenteral, pulmonary nasal and oral.

Suitable topical formulations include gels, creams, solutions,emulsions, carbohydrate polymers, biodegradable matrices thereof;vapors, mists, a aerosols, or other inhalants. The compounds of thepresent invention may be encapsulated in a wafer, wax, film or solidcarrier, including chewing gums. Permeation enhancers to aid intransport to movement across the epithelial layer are also known in theart and include, but are not limited to, dimethyl sulfoxide and glycols.

Optimal dosages to be administered may be determined by those skilled inthe art, and will vary with the particular compound in use, the strengthof the preparation, the mode of administration, and the advancement ofthe disease condition. Additional factors depending on the particularsubject being treated, including subject age, weight, gender, diet, andtime of administration, will result in a need to adjust dosages.Administration of the compound may be effected continuously orintermittently. One skilled in the art will readily appreciate thatappropriate biological assays will be used to determine the therapeuticpotential of the claimed compounds for treating α₂-mediated disorders,in particular the disorders described herein.

The present invention also provides a method for treating an α₂adrenergic receptor associated disorder in a subject, which comprisesadministering to the subject an amount of a compound effective to treatthe disorder, wherein the compound has the structure:

wherein X is CR₇; N; or N⁺O⁻;

wherein Y is O; CO; S; CR₃R₅; or NR₆;

wherein each R₂ is independently H; F; Cl; Br; I; —NO₂, —CN; straightchained or branched C₁-C₄ alkyl; C₁-C₄ monofluoroalkyl or C₁-C₄polyfluoroalkyl; straight chained or branched C₁-C₄ alkoxy; —OH;—(CH₂)_(q)OH; —COR₄; CO₂R₄; CONHR₄; phenyl; or benzyl;

wherein each R₃ is independently H; straight chained or branchedC₁-C₄alkyl; C₁-C₄ monofluoroalkyl or C₁-C₄ polyfluoroalkyl; straightchained or branched C₁-C₄ alkoxy; —(CH₂)_(q)OH; —OH; ═N—OR₄; COR₄;CO₂R₄; CONHR₄; phenyl; or benzyl;

wherein each R₄ is independently H; straight chained or branched C₁-C₄alkyl, C₁-C₄ monofluoroalkyl or C₁-C₄ polyfluoroalkyl; or phenyl;

wherein each R₅ is independently H; straight chained or branched C₁-C₄alkyl, C₁-C₄ monofluoroalkyl, or C₁-C₄ polyfluoroalkyl;

wherein R₆ is H; straight chained or branched C₁-C₄ alkyl; C₁-C₄monofluoroalkyl or C₁-C₄ polyfluoroalkyl; straight chained or branchedC₁-C₄ alkoxy; —CH₂CH₂ (CH₂)_(q)OH; COR₄; CO₂R₄; CONHR₄; phenyl; orbenzyl;

wherein each R₇ is independently H; —CN; straight chained or branchedC₁-C₄ alkyl; C₁-C₄ monofluoroalkyl or C₁-C₄ polyfluoroalkyl; straightchained or branched C₁-C₄ alkoxy; —OH; —(CH₂)_(q)OH; —COR₄; CO₂R₄;CONHR₄; phenyl; or benzyl;

wherein m and n are each independently 0, 1, 2 or 3, provided that m+nis 2 or 3;

wherein each p is independently 0, 1 or 2; and

wherein each q is independently 0, 1, 2 or 3;

or a pharmaceutically acceptable salt thereof.

The subject invention further provides a method for treating an α₂adrenergic receptor associated disorder in a subject, which comprisesadministering to the subject an amount of a compound effective to treatthe disorder, wherein the compound has the structure:

wherein each of Z1, Z2 and Z3 is N or CR₂, with the proviso that eitherone of Z1, Z2 or Z3 is N and the others of Z1, Z2 or Z3 are CR₂, or bothZ1 and Z3 are N and Z2 is CR₂;

wherein R₁ is H; F; straight chained or branched C₁-C₄ alkyl, C₁-C₄monofluoroalkyl or C₁-C₄ polyfluoroalkyl; straight chained or branchedC₁-C₄ alkoxy, —OH; or —(CH₂)_(q)OH;

wherein each R₂ is independently H; F; Cl; Br; I; —NO₂, —CN; straightchained or branched C₁-C₄ alkyl; C₁-C₄ monofluoroalkyl or C₁-C₄polyfluoroalkyl; straight chained or branched C₁-C₄ alkoxy; —OH;—(CH₂)_(q)OH; —COR₄; CO₂R₄; CONHR₄; phenyl; or benzyl;

wherein each R₄ is independently H; straight chained or branched C₁-C₄alkyl, C₁-C₄ monofluoroalkyl or C₁-C₄ polyfluoroalkyl; or phenyl; and

wherein q is each independently 0, 1, 2 or 3;

or a pharmaceutically acceptable salt thereof.

Examples of α₂ adrenergic receptor associated disorders which may betreated in accordance with the subject invention include, but are notlimited to, hypertension, pain, glaucoma, alcohol and drug withdrawal,rheumatoid arthritis, ischemia, migraine, cognitive deficiency,spasticity, diarrhea and nasal congestion.

In a specific embodiment of the present invention the α₂ adrenergicreceptor associated disorder is migraine headache, hypertension orglaucoma.

The present invention also provides a method for treating pain in asubject, which comprises administering to the subject an amount of acompound effective to treat the subject's pain, wherein the compound hasthe structure:

wherein X is CR₇; N; or N⁺O⁻;

wherein Y is O; CO; S; CR₃R₅; or NR₆;

wherein each R₂ is independently H; F; Cl; Br; I; —NO₂, —CN; straightchained or branched C₁-C₄ alkyl; C₁-C₄ monofluoroalkyl or C₁-C₄polyfluoroalkyl; straight chained or branched C₁-C₄ alkoxy; —OH;—(CH₂)_(q)OH; —COR₄; CO₂R₄; CONHR₄; phenyl; or benzyl;

wherein each R₃ is independently H; straight chained or branched C₁-C₄alkyl; C₁-C₄ monofluoroalkyl or C₁-C₄ polyfluoroalkyl; straight chainedor branched C₁-C₄ alkoxy; —(CH₂)_(q)OH; —OH; ═N—OR₄; COR₄; CO₂R₄;CONHR₄; phenyl; or benzyl;

wherein each R₄ is independently H; straight chained or branched C₁-C₄alkyl, C₁-C₄ monofluoroalkyl or C₁-C₄ polyfluoroalkyl; or phenyl;

wherein each R₅ is independently H; straight chained or branched C₁-C₄alkyl, C₁-C₄ monofluoroalkyl, or C₁-C₄ polyfluoroalkyl;

wherein R₆ is H; straight chained or branched C₁-C₄ alkyl; C₁-C₄monofluoroalkyl or C₁-C₄ polyfluoroalkyl; straight chained or branchedC₁-C₄ alkoxy; —CH₂CH₂(CH₂)_(q)OH; COR₄; CO₂R₄; CONHR₄; phenyl; orbenzyl;

wherein each R₇ is independently H; —CN; straight chained or branchedC₁-C₄ alkyl; C₁-C₄ monofluoroalkyl or C₁-C₄ polyfluoroalkyl; straightchained or branched C₁-C₄ alkoxy; —OH; —(CH₂)_(q)OH; —COR₄; CO₂R₄;CONHR₄; phenyl; or benzyl;

wherein m and n are each independently 0, 1, 2 or 3, provided that m+nis 2 or 3;

wherein each p is independently 0, 1 or 2; and

wherein each q is independently 0, 1, 2 or 3;

or a pharmaceutically acceptable salt thereof.

The present invention also provides a method for treating pain in asubject, which comprises administering to the subject an amount of acompound effective to treat the subject's pain, wherein the compound hasthe structure:

wherein each of Z1, Z2 and Z3 is N or CR₂, with the proviso that eitherone of Z1, Z2 or Z3 is N and the others of Z1, Z2 or Z3 are CR₂, or bothZ1 and Z3 are N and Z2 is CR₂;

wherein R₁ is H; F; straight chained or branched C₁-C₄ alkyl, C₁-C₄monofluoroalkyl or C₁-C₄ polyfluoroalkyl; straight chained or branchedC₁-C₄ alkoxy, —OH; or —(CH₂)_(q)OH;

wherein each R₂ is independently H; F; Cl; Br; I; —NO₂, —CN; straightchained or branched C₁-C₄ alkyl; C₁-C₄ monofluoroalkyl or C₁-C₄polyfluoroalkyl; straight chained or branched C₁-C₄ alkoxy; —OH;—(CH)_(q)OH; —COR₄; CO₂R₄; CONHR₄; phenyl; or benzyl;

wherein each R₄ is independently H; straight chained or branched C₁-C₄alkyl, C₁-C₄ monofluoroalkyl or C₁-C₄ polyfluoroalkyl; or phenyl; and

wherein q is each independently 0, 1, 2 or 3;

or a pharmaceutically acceptable salt thereof.

This invention will be better understood from the Experimental Detailswhich follow. However, one skilled in the art will readily appreciatethat the specific methods and results discussed are merely illustrativeof the invention as described more fully in the claims which followthereafter.

EXPERIMENTAL DETAILS

The compounds of Examples 1-31 may be obtained using the methodsdepicted in Schemes 1-4, except for example 2 which was obtained bybromination of example 1, and for examples 27 and 28 which were preparedfrom example 21 by hydrogen peroxide oxidation and by bromination,respectively. Only one amine, 5-aminoindan, was commercially availableand was used to prepare example 1. Upon bromination, 5-aminoindanprovided the amine precursor to example 3. The other amines wereobtained from the corresponding nitro compounds by hydrogenation ortin(II) chloride reduction (Scheme 1). All of the nitropyridines weresynthesized by the reaction of a ketone with1-methyl-3,5-dinitro-2-pyridone which was in turn obtained from1-methyl-2-pyridone by nitration (Scheme 2). The other nitro compoundswere either commercially available or obtained from functionalization ofcommercially available nitro compounds as illustrated in Scheme 3.Exceptions include example 11 whereby the nitro group was generated bynitration. The synthesis of examples 29-31 is depicted in Scheme 4.

The compounds of Examples 32-44 may be obtained using the methodsdepicted in Schemes 5 and 6. Examples 32-38 were prepared using thegeneral scheme shown in Scheme 5, and Examples 39-44 were preparedaccording to Scheme 6.

Abbreviations in Schemes 5 and 6:

n-BuLi n-butyl lithium DMF dimethylformamide LDA lithium diisopropylamide Me methyl Et ethyl Ph phenyl RT room temperature DMSO dimethylsuifoxide AcCl acetyl chloride Py pyridine THF tetrahydrofuran TBDMSt-butyl dimethylsilyl

EXAMPLE 1 2-(5-Indanylamino)-2-imidazoline

A mixture of 5-aminoindan (200 mg, 1.50 mmol) and 2-imidazolinesulfonicacid (450 mg, 3.00 mmol) in isobutyl alcohol (5 mL) was heated at refluxfor 3 h and then stirred overnight. The solvent was removed to give adark oil. It was flash chromatographed over silica gel(EtOAc:MeOH:Et₃N=6:2:1) to afford a yellow solid. The solid wasredissolved in dichloromethane, and washed with saturated aqueousNa₂CO₃. The organic layer was dried and concentrated to give yellowcrystals (220 mg, 73% yield): mp 41-42° C.; EIMS m/z=201 (M⁺). Anal.Calcd. for C₁₂H₁₅N₃ 4/5H₂O: C, 66.82; H, 7.74; N, 19.48. Found: C,66.77; H, 7.31; N, 19.24.

EXAMPLE 2 2-(6-Bromo-5-indanylamino)-2-imidazoline hydrobromide

To a solution of 2-(5-Indanylamino)-2-imidazoline (100 mg, 0.497 mmol)in acetic acid (7 mL) was added a solution of bromine (153 mg, 0.957mmol) in acetic acid (1 mL). The resulting mixture was stirred for 5min, and the solvent was removed. The residue was flash chromatographedover silica gel (EtOAc:MeOH:Et₃N=6:2:1) to afford a solid, which wasrecrystallized from dichloromethane/hexane to give a beige solid (25 mg,14% yield): mp 220-221° C.; HRMS (EI) calcd. for C₁₂H₁₄N₃Br 279.0371,obsd. 279.0383. Anal. Calcd. for C₁₂H₁₄N₃BrH·Br2/3H₂O: C, 38.63; H,4.41; N, 11.26; Br, 42.83. Found: C, 39.10; H, 4.21; N, 10.87; Br,42.37.

EXAMPLE 3 2-(4,6-Dibromo-5-indanylamino)-2-imidazoline

4,6-Dibromo-5-aminoindane. To a solution of 5-aminoindane (1.00 g, 7.51mmol) in acetic acid (40 mL) was added bromine (3 mL). The resultingmixture was stirred for an hour and then concentrated by half.Chloroform was added to give a precipitate. The solid was isolated, andwashed with chloroform to afford a lightly tinted solid (2.06 g, 94%yield): mp 220-221° C.; ¹H NMR (300 MHz, CD₃OD) d 2.07 (m, 2H). 2.90 (m,4H). 7.33 (s, 1H).

3-Acetyl-2-(4,6-dibromo-5-indanylamino)-2-imidazolinone. A mixture ofthe above solid (200 mg, 0.687 mmol) and N-acetyl-2-imidazolidone (106mg, 0.827 mmol) in phosphorus oxychloride (5 mL) was stirred at 50° C.for 48 h. The solvent was removed. The residue was dissolved indichloromethane (5 mL) and washed with 1 N aqueous NaOH solution (2×5mL). The organic layer was dried (Na₂SO₄), filtered and concentrated togive a white solid (270 mg, 99%). This solid (220 mg, 0.548 mmol) washeated in water (5 mL) at reflux for 4 h, and then cooled to roomtemperature. The resulting solution was washed with CH₂Cl₂, and basifiedwith 1 N aqueous NaOH until pH=8. The aqueous layer was then extractedwith EtOAc (2×10 mL), and the combined extracts were dried andconcentrated to yield a white solid (91 mg, 46% yield): mp 163-164° C.;CIMS m/e=360 (MH⁺); Anal. Calcd. for C₁₂H₁₃N₃Br₂: C, 40.14; H, 3.65, N;11.70; Br, 44.51,. Found: C, 40.42; H, 3.95; N, 11.41; Br, 44.54.

EXAMPLE 4 2-(1,2,3,4-Tetrahydro-1-oxo-naphth-7-yl)amino-2-imidazoline

7-Amino-1-tetralone. A suspension of 7-nitro-1-tetralone (2.00 g, 10.5mmol) in MeOH (20 mL) was treated with 10% Pd-C (100 mg) andhydrogenated at 1 atm for 5 h. Filtration through Celite gave a brownsolid (1.38 g). It was suspended in CHCl₃ and flash chromatographed oversilica gel (69 g) eluting with EtOAc/hexane (1:2) to afford a tan solid(0.62 g, 37% yield): mp 137-138° C.

2-(1,2,3,4-Tetrahydro-1-oxo-naphth-7-yl)amino-2-imidazoline. The abovesolid (150 mg, 0.93 mmol) was suspended in isobutyl alcohol (5 mL),treated with 2-imidazoline sulfonic acid (280 mg, 1.86 mmol) and heatedat reflux overnight. More 2-imidazoline sulfonic acid (70 mg) was addedand reflux was continued overnight. The solvent was evaporated off togive a brown oil. It was dissolved in CHCl₃-MeOH and flashchromatographed over silica gel (17 g) eluting with EtOAc/MeOH/Et₃N(10:2:1) to afford a pale yellow foam (157 mg, 74% yield). A portion(151 mg) was dissolved in EtOH and treated with fumaric acid (39 mg) inEtOH to give some off-white crystals (100 mg): mp 198-201° C. (dec.);CIMS, m/e=230 (MH⁺). Anal. Calcd. for C₁₃H₁₅N₃O·C₄H₄O₄: C, 59.12; H,5.55; N, 12.17. Found: C, 58.91; H, 5.50; N, 12.03.

EXAMPLE 52-(8-Bromo-1,2,3,4-Tetrahydro-1-oxo-naphth-7-yl)amino-2-imidazoline

7-Amino-8-bromo-1-tetralone. 7-Amino-1-tetralone (457 mg, 2.83 mmol) wasdissolved in acetic acid (8 mL) and treated with bromine (150 mL, 2.91mmol) dropwise. After 10 min., more bromine (17 mL) was added. Then thesolvent was evaporated off to give a light brown solid. It waspartitioned between Na₂CO₃ solution and EtOAc. From the organic phasewas obtained a semi-solid (696 mg). It was dissolved in CHCl₃ and flashchromatographed over silica gel 50 g) eluting with EtOAc/hexane (1:4) toafford a yellow solid (320 mg, 47% yield): mp 93-96° C.

2-(8-Bromo-1,2,3,4-Tetrahydro-1-oxo-naphth-7-yl)amino-2-imidazoline. Theabove solid (100 mg, 0.42 mmol) was added to a mixture of1-acetyl-2-imidazolidone (63 mg, 0.49 mmol) and POCl₃ (3 mL). Themixture was heated at 50-60° C. overnight. Then the solvent wasevaporated off. The residue was dissolved in CH₂Cl₂ (8 mL) and washedwith 1N NaOH twice. The organic layer was dried (MgSO₄), filtered andconcentrated to give an off-white foam (123 mg). It was heated at refluxin water (5 mL) for 2.5 h. The cooled mixture was filtered and thefiltrate was basified with NaOH and Na₂CO₃ solutions to give a yellowsolid (47 mg, 37% yield) which was filtered off and washed with water.It was dissolved in MeOH and treated with fumaric acid (17 mg) in MeOH.Then the solvent was evaporated off. The residue was triturated withMeOH to afford brown crystals (35 mg): mp 204-207° C. (dec.); CIMS,m/e=308, 310 (MH⁺). Anal. Calcd. for C₁₃H₁₄BrN₃O·C₄H₄O₄: C, 48.13; H,4.28; N, 9.90. Found: C, 48.37; H, 4.27; N, 9.82.

EXAMPLE 62-(1,2,3,4-Tetrahydro-1-hydroxy-naphth-7-yl)amino-2-imidazoline

1-Hydroxy-7-nitro-tetralin. A suspension of 7-nitro-1-tetralone (2.00 g,10.5 mmol) in EtOH (15 mL) was cooled by an ice water bath and treatedwith NaBH₄ (0.40 g, 10.6 mmol). The mixture was stirred at roomtemperature for 2 h and then poured into ice water (50 mL) and extractedwith EtOAc (3×20 mL). The extract was washed with NaCl solution, dried(MgSO₄). filtered and concentrated to give a white solid (1.92 g, 95%yield).

7-Amino-1-hydroxy-tetralin. The above solid (0.92 g, 4.76 mmol) wasdissolved in dry MeOH (10 mL), treated with 10% Pd-C (100 mg) andhydrogenated at 1 atm for 4 h. The mixture was filtered through Celiteto give an orange solid (0.777 g). It was dissolved in CHCl₃ and flashchromatographed over silica gel (42 g) eluting with EtOAc/hexane (1:2and then 1:1) to afford a pinkish solid (691 mg, 89% yield).

2-(1,2,3,4-Tetrahydro-1-hydroxy-naphth-7-yl)amino-2-imidazoline. Theabove amine (200 mg, 1.23 mmol) was mixed with 2-imidazolinesulfonicacid (368 mg, 2.45 mmol) in isobutyl alcohol (6 mL) and heated at refluxovernight. The solvent was removed, and the residue was dissolved inEtOAc/MeOH/Et₃N (5:5:1) and flash chromatographed over silica gel (18 g)eluting with the same solvent to give a white foam (225 mg, 79% yield).It was dissolved in EtOH and treated with fumaric acid (113 mg) in EtOH.Upon dilution with EtOAc and standing at −15° C., the solution give awhite solid (241 mg): mp 180-182° C. (dec.). Anal. Calcd. forC₁₃H₁₇N₃O·C₄H₄O₄: C, 58.78; H, 6.09; N, 12.10. Found: C, 58.98; H, 6.39;N, 11.93.

EXAMPLE 7 2-(1,2,3,4-Tetrahydro-1-methyl-naphth-7-yl)amino-2-imidazoline

1-Methylene-7-nitro-tetralin. 7-Nitro-1-tetralone (1.00 g, 5.23 mmol)was dissolved in dry THF (5 mL) and added to a solution ofmethyltriphenylphosphonium bromide (2.00 g, 5.60 mmol) andn-butyllithium (2.5 M in hexanes, 2.2 mL, 5.5 mmol) in THF (10 mL)cooled by an ice water bath. The mixture was allowed to warm to roomtemperature and stirred overnight. It was poured into ice water (45 mL)and extracted with EtOAc (3×20 mL). The extract was washed with NaClsolution, dried (MgSO₄), filtered and concentrated to give a black solid(1.504 g). It was dissolved in CHCl₃ and flash chromatographed oversilica gel (65 g) eluting with EtOAc/hexane (1:20) to afford a whitesolid (263 mg, 27% yield): mp 45-47° C.

2-(1,2,3,4-Tetrahydro-1-methyl-naphth -7-yl)amino-2-imidazoline. Theabove solid was dissolved in dry MeOH (5 mL), treated with 10% Pd-C (50mg) and hydrogenated at 1 atm for 4 h. The mixture was then filteredthrough Celite to afford a light orange oil (211 mg). It was mixed with2-imidazolinesulfonic acid (393 mg, 2.62 mmol) in isobutyl alcohol (6mL) and heated at reflux overnight. The solvent was removed to give alight blue oil which was dissolved in CHCl₃ and flash chromatographedover silica gel (30 g) eluting with EtOAc/MeOH/Et₃N (5:2:0.7) to give awhite foam (177 mg, 56% yield). It was dissolved in EtOH and treatedwith fumaric acid (89 mg) in EtOH. Upon refrigeration, the solutionafforded a white solid (202 mg): mp 185-187° C. (dec.); CIMS m/e=230(MH⁺). Anal. Calcd. for C₁₄H₁₉N₃·C₄H₄O₄·1/10H₂O: C, 62.27; H, 6.73; N,12.10. Found: C, 62.15; H, 6.65; N, 11.81.

EXAMPLE 82-(1,2,3,4-Tetrahydro-1-methoxyimino-naphth-7-yl)amino-2-imidazoline

1-Methoxyimino-7-nitro-tetralin. 7-Nitro-tetralone (1.00 g, 5.23 mmol)was suspended in EtOH (10 mL), cooled by an ice water bath and treatedwith methoxylamine hydrochloride (0.52 g, 6.23 mmol) and sodiumbicarbonate (0.57 g, 6.78 mmol). The mixture was stirred at roomtemperature for 1 h before ice water (50 mL) was added. A precipitateformed which was filtered off to give a white solid (1.10 g, 95% yield).This solid contained two geometric isomers in a ratio of 7:1. It wasdissolved in CHCl₄/CHCl₃ and flash chromatographed over silica gel (50g) eluting with EtOAc/hexane (1:20) to afford the major isomer as awhite solid. It was recrystallized from hot EtOAc to give colorlesscrystals (556 mg): mp 128-131° C.

7-Amino-1-Methoxyimino-tetralin. 1-Methoxyimino-7-nitro-tetralin (252mg, 1.14 mmol) was treated with 10% Pd-C (25 mg) in MeOH (5 mL) andhydrogenated at 1 atm for 2 h. The mixture was filtered through Celiteto give a yellowish solid (208 mg, 96% yield).

2-(1,2,3,4-Tetrahydro-1-methoxyimino-naphth-7-yl)amino-2-imidazoline.The above solid (206 mg, 1.08 mmol) was mixed with 2-imidazolinesulfonicacid (325 mg, 2.16 mmol) in isobutyl alcohol (7 mL) and heated at refluxfor two days. The solvent was removed and the residue was dissolved inCHCl₃ and flash chromatographed over silica gel (18 g) eluting withEtOAc/MeOH/Et₃N (10:2:0.6) to give a white foam (250 mg, 89% yield). Itwas dissolved in EtOH and treated with fumaric acid (113 mg) in EtOH.Upon refrigeration, the solution afforded a white solid (152 mg): mp201-202° C. (dec.). Anal. Calcd. for C₁₄H₁₈N₄O C₄H₄O₄: C, 57.75; H,5.92; N. 14.96. Found: C, 57.54; H, 5.79; N, 14.68.

EXAMPLE 9 2-(1-Acetyl-indolin-5-yl)amino-2-imidazoline

1-Acetyl-5-nitroindoline (1.87 g, 9.07 mmol) was suspended in dry MeOH(40 mL), treated with 10% Pd-C (157 mg) and hydrogenated at 1 atm for 5h. The mixture was filtered through Celite to give a light brown solid(1.33 g, 83% yield). A portion (207 mg, 1.17 mmol) was mixed with2-imidazolinesulfonic acid (349 mg, 2.32 mmol) in isobutyl alcohol (8mL) and heated at reflux for 2 days. Evaporation of the solvent gave alight brown oil which was dissolved in EtOAc/MeOH/Et₃N (25:15:2) andflash chromatographed over silica gel (15 g) eluting with the samesolvent to afford a light brown foam. It was again dissolved inEtOAc/MeOH/Et₃N (10:2:0.6) and flash chromatographed over silica geleluting with the same solvent to give a yellow solid (82 mg, 29% yield).It was dissolved in MeOH/EtOH and treated with fumaric acid (38 mg) inEtOH to afford light brown crystals (67 mg): mp 200-203° C. (dec.).Anal. Calcd. for C₁₃H₁₆N₄O C₄H₄O₄: C, 56.66; H, 5.59; N, 15.55. Found:C, 56.39; H, 5.40; N, 15.38.

EXAMPLE 10 2-(1-Ethyl-indolin-5-yl)amino-2-imidazoline

1-Ethyl-5-nitro-indoline. 1-Acetyl-5-nitro-indoline (1.00 g, 4.85 mmol)was added to borane-THF complex (1 M, 10 mL, 10 mmol). The mixture washeated at reflux for 4 h. With ice-water bath cooling, the mixture wasslowly treated with 6 N HCl (4 mL). Then the mixture was heated at 50°C. for 1 h. The organic solvent was evaporated off and the resultingsuspension was filtered to give an orange solid (1.02 g) which waswashed with water: mp 97-98° C.

2-(1-Ethyl-indolin-5-yl)amino-2-imidazoline. The above solid (400 mg,2.08 mmol) was suspended in MeOH (8 mL), treated with 10% Pd-C (40 mg)and hydrogenated at 1 atm for 2 h. The mixture was filtered throughCelite to give an oil (270 mg). It was mixed with 2-imidazolinesulfonicacid (500 mg, 3.33 mmol) in isobutyl alcohol (8 mL) and heated at refluxovernight. The solvent was removed to give a dark oil. It was dissolvedin CHCl₁₃ and flash chromatographed over silica gel (15 g) eluting withEtOAc/MeOH/Et₃N (20:4:1) to give a dark foam (157 mg). It was dissolvedin EtOH and treated with fumaric acid (79 mg) in EtOH to give, uponrefrigeration, an orange solid (137 mg, 19% yield): mp 198-200° C.(dec.). Anal. Calcd. for C₁₃H₁₄·C₄H₄O₄: C, 58.95; H. 6.40; N, 16.17.Found: C, 58.83; H, 6.39; N, 16.03.

EXAMPLE 11 2-(6-Nitro-indan-5-yl)amino-2-imidazoline

5-Acetamido-6-nitro-indan. 5-Amino-indan (3.00 g, 22.53 mmol) was addedslowly to acetic anhydride (10 mL) cooled by an ice water bath. After 15min., 70% HNO₃ (3 mL, 46.99 mmol) was carefully added dropwise so thatthe temperature remained below 26° C. The mixture was allowed to slowlywarm to room temperature and stirred for 2 days. It was then treatedwith ice water (60 mL) and extracted with EtOAc (3×20 mL). The extractwas washed with water, Na₂CO₃ solution, dried (MgSO4), filtered andconcentrated to give a dark oil (3.51 g). It was dissolved in CHCl₃ andflash chromatographed over silica gel (180 g) eluting with EtOAc/hexane(1:10) to afford a yellowish orange solid (1.43 g, 29% yield): mp100-104° C.

5-Amino-6-nitro-indan. The above solid (203 mg, 0.92 mmol) was heated atreflux in 4N HCl (4 mL) for 6 h. The mixture was basified with Na₂CO₃solution and extracted with EtOAc (3×4 mL) to give an orange solid (156mg, 95% yield).

2-(6-Nitro-indan-5-yl)amino-2-imidazoline. The above solid (153 mg, 0.86mmol) was dissolved in CHCl₃ (3 mL), cooled by an ice water bath, andtreated with thiophosgene (80 mL, 1.05 mmol) and then NaHCO₃ (220 mg,2.62 mmol) in water (3 mL). The mixture was stirred at room temperaturefor 6 h before more thiophosgene (80 mL) and NaHCO₃ (220 mg) were added.The mixture was stirred overnight and then extracted with CHCl₃ (2×4 mL)to give an orange oil (172 mg, 91% yield). It was suspended in MeOH (5mL) and treated with ethylenediamine (250 mL, 3.74 mmol). The mixturewas heated at reflux for 5 h before the solvent was evaporated off togive a dark oil. It was suspended in CHCl₃ and flash chromatographedover silica gel (17 g) eluting with EtOAc/hexane/Et₃N (15:5:1) to affordan orange solid (130 mg, 68% yield). A portion (64 mg) was dissolved inEtOH and treated with fumaric acid (30 mg) in EtOH to give a yellowsolid (57 mg): mp 213-214° C. (dec.). Anal. Calcd. forC₁₂H₁₄N₄O₂·3/4C₄H₄O1/2H₂O: C, 52.63; H, 5.30; N, 16.37. Found: C, 52.51;H, 5.11; N, 16.16.

EXAMPLE 122-(5,6,7,8-Tetrahydro-6-methyl-quinolin-3-yl)amino-2-imidazoline

1-Methyl-3,5-dinitro-2-pyridone. To a mixture of 1-methyl-2-pyridone(16.3 g, 0.15 mol) and sulfuric acid (150 mL) being heated at 100° C.was added nitric acid (57 mL) in portions of 1-2 mL. The temperatureduring the addition of the acid was kept at 95-110° C. The reactionmixture was then heated at 100° C. for 16 h, during which timeconsiderable amounts of brown fumes were evolved. The reaction mixturewas then allowed to cool to room temperature and was poured into icewater (600 mL). The product (8.2 g, 28% yield) was filtered off andwashed with water until free of acids.

5,6,7,8-Tetrahydro-6-methyl-3-nitro-quinoline. 4-Methylcyclohexanone(170 mg, 1.52 mmol) was mixed with 1-methyl-3,5-dinitro-2-pyridone (300mg, 1.51 mmol) in 1M methanolic ammonia (30 mL, 30 mmol). The solutionwas heated at gentle reflux for 3 h. Evaporation of the solvent gave anorange residue which was suspended in CHCl₃ and flash chromatographedover silica gel (16 g) eluting with EtOAc/hexane (1:10) to afford awhite solid (211 mg, 73% yield): mp 50-52° C.

3-Amino-5,6,7,8-tetrahydro-6-methylquinoline. The above solid (211 mg,1.10 mmol) was dissolved in MeOH (4 mL), treated with 10% Pd-C (20 mg)and hydrogenated at 1 atm for 3 h. Filtration through Celite gave asticky white solid (176 mg, 99% yield).

2-(5,6,7,8-Tetrahydro-6-methyl-quinolin-3-yl)amino-2-imidazoline. Theabove solid (174 mg, 1.07 mmol) was mixed with 2-imidazolinesulfonicacid (322 mg, 2.14 mmol) in isobutyl alcohol (5 mL) and heated at refluxfor 2.5 days. The solvent was evaporated off to give a residue which wasdissolved in CHCl₃ and flash chromatographed over silica gel (19 g)eluting with EtOAc/MeOH/Et₃N (20:3:1) to afford an off-white solid (247mg, 100% yield). It was dissolved in EtOH and treated with fumaric acid(125 mg) in EtOH. Upon refrigeration, the solution gave a white solid(98 mg): mp 192-195° C. (dec.). Anal. Calcd. for C₁₃H₁₈N₄·1.4C₄H₄O₄: C,56.87; H, 6.06; N, 14.26. Found: C, 56.77; H. 6.00; N, 14.55.

EXAMPLE 132-(5,6,7,8-Tetrahydro-7-methyl-quinolin-3-yl)amino-2-imidazoline

5,6,7,8-Tetrahydro-7-methyl-3-nitro-quinoline. 3-Methylcyclohexanone(0.56 g, 4.99 mmol) was mixed with 1-methyl-3,5-dinitro-2-pyridone(1.00g, 5.02 mmol) in 1M methanolic ammonia (50 mL, 50 mmol) and heated atreflux overnight. The solvent was evaporated off and the residue wassuspended in CHCl₃ and flash chromatographed over silica gel (43 g)eluding with EtOAc/hexane (1:10) to afford a white solid (515 mg, 63%yield): mp 55-56° C.

3-Amino-5,6,7,8-tetrahydro-7-methylquinoline. The above solid (245 mg,1.51 mmol) was dissolved in MeOH (5 mL), treated with 10% Pd-C (27 mg)and hydrogenated at 1 atm for 2 h. Filtration through Celite gave acolorless oil (212 mg).

2-(5,6,7,8-Tetrahydro-7-methyl-quinolin-3-yl)amino-2-imidazoline. Theabove amine (208 mg, 1.57 mmol) was mixed with 2-imidazolinesulfonicacid (470 mg, 3.13 mmol) in isobutyl alcohol (7 mL) and heated at refluxfor 2 days. The solvent was evaporated off to give a residue which wasdissolved in CHCl₃ and flash chromatographed over silica gel (19 g)eluting with EtOAc/MeQH/Et₃N (20:3:1) to afford a white solid (289 mg,92% yield). A portion (135 mg) was dissolved in EtOH and treated withfumaric acid (157 mg) in EtOH to give white crystals (162 mg): mp197-198° C. (dec.). Anal. Calcd. for C₁₃H₁₃N₄·2C₄H₄O: C, 54.54; H, 5.67;N, 12.12. Found: C, 54.25; H, 5.86; N, 11.91.

EXAMPLE 142-(5,6,7,8-Tetrahydro-8-methyl-quinolin-3-yl)amino-2-imidazoline

5,6,7,8-Tetrahydro-8-methyl-3-nitro-quinoline. 2-Methylcyclohexanone(170 mg, 1.52 mmol) was mixed with 1-methyl-3,5-dinitro-2-pyridone (296mg, 1.49 mmol) in 1M methanolic ammonia (30 mL, 30 mmol) and heated atreflux for 3 h. The solvent was evaporated off and the residue wassuspended in CHCl₃ and flash chromatographed over silica gel (19 g)eluting with EtOAc/hexane (1:10) to afford a white solid (213 mg, 75%yield): mp 61-63° C.

3-Amino-5,6,7,8-tetrahydro-8-methylquinoline. The above solid (211 mg,1.10 mmol) was dissolved in MeOH (4 mL), treated with 10% Pd-C (20 mg)and hydrogenated at 1 atm for 3 h. Filtration through Celite gave acolorless oil (180 mg, 101% yield).

2-(5,6,7,8-Tetrahydro-8-methyl-quinolin-3-yl)amino-2-imidazoline. Theabove amine (178 mg, 1.10 mmol) was mixed with 2-imidazolinesulfonicacid (322 mg, 2.14 mmol) in isobutyl alcohol (5 mL) and heated at refluxfor 2.5 days. The solvent was evaporated off to give a residue which wasdissolved in CHCl₃ and flash chromatographed over silica gel (18 g)eluting with EtOAc/MeOH/Et₃N (20:3:1) to afford a pale brown foam (206mg, 82% yield). It was dissolved in EtOH and treated with fumaric acid(208 mg) in EtOH. Upon refrigeration, the solution gave a white solid(135 mg): mp 155-160° C. (dec.). Anal. Calcd. for C₁₃H₁₈N₄·1.75C₄H₄O₄:C, 55.42; H, 5.81; N, 12.93. Found: C, 55.44; H, 5.88; N, 13.03.

EXAMPLE 15 (5R),(8S)-2-(5,6,7,8-Tetrahydro-8-isopropyl-5-methyl-quinolin-3-yl)amino-2-imidazoline

(5R)), (8S)-3-Amino-5,6,7,8-tetrahydro-8-isopropyl-5-methylquinoline.(−)-Menthone (390 mg, 2.53 mmol) was mixed with1-methyl-3,5-dinitro-2-pyridone (500 mg, 2.51 mmol) in 1M methanolicammonia (50 mL, 50 mmol) and heated at reflux overnight. The solvent wasevaporated off and the residue was dissolved in CHCl₃ and flashchromatographed over silica gel (37 g) eluting with EtOAc/hexane (1:20)to afford a colorless oil (248 mg, 1.06 mmol). It was dissolved in MeOH(5 mL), treated with 10% Pd-C (27 mg) and hydrogenated at 1 atm for 2 h.Filtration through Celite gave a pale yellow solid (207 mg). It waspartitioned between CH₂Cl₂ and 2N HCl. The organic layer was furtherextracted with 2N HCl before the aqueous layer was basified with Na₂CO₃solution and extracted with CH₂Cl₂ to afford a white solid (123 mg, 24%yield).

(5R),(8S)-2-(5,6,7,8-Tetrahydro-8-isopropyl-5-methyl-quinolin-3-yl)amino-2-imidazoline.The above amine (119 mg, 0.58 mmol) was mixed with 2-imidazolinesulfonicacid (180 mg, 1.20 mmol) in isobutyl alcohol (5 mL) and heated at refluxfor 2 days. The solvent was evaporated off to give a residue which wasdissolved in CHCl₃ and flash chromatographed over silica gel (17 g)eluting with EtOAc/MeOH/Et₃N (20:3:1) to afford a white solid (129 mg,81% yield). It was dissolved in EtOH and treated with fumaric acid (110mg) in EtOH. Upon addition of ether and refrigeration, the solution gavewhite crystals (43 mg): mp 151-154° C. Anal. Calcd. for C₁₆H₂₄N₄1.6C₄H₄O₄: C, 58.73; H, 6.69; N, 12.23. Found: C, 58.41; H, 7.04; N,12.24.

EXAMPLE 162-(5,6,7,8-Tetrahydro-6,6-dimethyl-quinolin-3-yl)amino-2-imidazoline

5,6,7,8-Tetrahydro-6,6-dimethyl-3-nitro-quinoline.4,4-Dimethyl-2-cyclohexen-1-one (500 mL, 3.80 mmol) was mixed with 10%Pd-C (50 mg) and hydrogenated at 1 atm in MeOH (5 mL) for 2 h.Filtration through Celite gave a colorless oil (430 mg). It was mixedwith 1-methyl-3,5-dinitro-2-pyridone (679 mg, 3.41 mmol) in 1Mmethanolic ammonia (68 mL, 68 mmol) and heated at reflux for 3 h. Thesolvent was evaporated off and the residue was suspended in CHCl₃ andflash chromatographed over silica gel (30 g) eluting with EtOAc/hexane(1:15) to afford a white solid (195 mg, 25% yield): mp 99-101° C.

3-Amino-5,6,7,8-tetrahydro-6,6-dimethylquinoline. The above solid (195mg, 0.95 mmol) was dissolved in MeOH (4.5 mL), treated with 10% Pd-C (20mg) and hydrogenated at 1 atm for 2 h. Filtration through Celite gave asticky greyish solid (162 mg, 97% yield).

2-(5,6,7,8-Tetrahydro-6,6-dimethyl-quinolin-3-yl)amino-2-imidazoline.The above amine (162 mg, 0.92 mmol) was mixed with 2-imidazolinesulfonicacid (276 mg, 1.84 mmol) in isobutyl alcohol (5 mL) and heated at refluxfor 3 days. The solvent was evaporated off to give a residue which wasdissolved in CHCl₃ and flash chromatographed over silica gel (19 g)eluting with EtOAc/MeOH/Et₃N (10:2:1) to afford a white foam (196 mg,87% yield). It was dissolved in EtOH and treated with fumaric acid (186mg) in EtOH. The solvent was removed and the residue was recrystallizedfrom 2-propanol to afford a pale yellow solid (158 mg): mp 186-188° C.(dec.). Anal. Calcd. for C₁₄H_(33l N) ₄·1.5C₄H₄O₄: C, 57.41; H, 6.26; N,13.39. Found: C, 57.24; H, 6.26; N, 13.15.

EXAMPLE 172-(5,6,7,8-Tetrahydro-8,8-dimethyl-quinolin-3-yl)amino-2-imidazoline

5,6,7,8-Tetrahydro-8,8-dimethyl-3-nitro-quinoline.2,2-Dimethyl-2-cyclohexanone (317 mg, 2.51 mmol) was mixed with1-methyl-3,5-dinitro-2-pyridone (500 mg, 2.51 mmol) in 1M methanolicammonia (50 mL, 53 mmol) and heated at reflux overnight. The solvent wasevaporated off and the residue was suspended in CHCl₃ and flashchromatographed over silica gel (33 g) eluting with EtOAc/hexane (1:20)to afford a colorless oil (414 mg, 80% yield).

3-Amino-5,6,7,8-tetrahydro-6,6-dimethylquinoline. The above oil (410 mg,1.99 mmol) was dissolved in MeOH (6 mL), treated with 10% Pd-C (42 mg)and hydrogenated at 1 atm for 5 h. Filtration through Celite gave asticky pinkish solid (320 mg, 91% yield).

2-(5,6,7,8-Tetrahydro-8,8-dimethyl-quinolin-3-yl)amino-2-imidazoline.The above amine (175 mg, 0.99 mmol) was mixed with 2-imidazolinesulfonicacid (300 mg, 2.00 mmol) in isobutyl alcohol (6 mL) and heated at refluxfor 2 days. The solvent was evaporated off to give a residue which wasdissolved in CHCl₃ and flash chromatographed over silica gel (19 g)eluting with FtOAc/MeOH/Et.N (20:3:1) to afford a sticky white solid(169 mg, 70% yield). It was dissolved in EtOH and treated with fumaricacid (160 mg) in EtOH. Upon the addition of ether and refrigeration, thesolution gave white crystals (145 mg): mp 185-186° C. (dec.). Anal.Calcd. for C₁₄H₂₀N₄ 1.5C₄H₄O₄: C, 57.41; H, 6.26; N, 13.39. Found: C,57.24; H, 6.57; N, 13.10.

EXAMPLE 18(R)-2-(5,6,7,8-Tetrahydro-6,8-dimethylmethano-quinolin-3-yl)amino-2-imidazoline

(R)-3-Amino-5,6,7,8-Tetrahydro-6,8-dimethylmethano-quinoline.(R)-(+)-Nopinone (347 mg, 2.51 mmol) was mixed with1-methyl-3,5-dinitro-2-pyridone (500 mg, 2.51 mmol) in 1M methanolicammonia (5 mL, 50 mmol) and heated at reflex overnight. The solvent wasevaporated off and the residue was suspended in CHCl₃. The solublefraction was flash chromatographed over silica gel (20 g) eluting withEtOAc/hexane (1:10) to afford a colorless oil (303 mg). A portion (298mg, 1.37 mmol) was dissolved in MeOH (5 mL), treated with 10% Pd-C (30mg) and hydrogenated at 1 atm for 2 h. Filtration through Celite gave apale yellow oil (178 mg). It was partitioned between 2N HCl and CH₂Cl₂.The aqueous layer was washed once more with CH₂Cl₂ before it wasbasified with Na₂CO₂ solution and extracted with CH₂Cl₂ (3×4 mL) to givea white solid (45 mg, 10% yield).

(R)-2-(5,6,7,8-Tetrahydro-6,8-dimethylmethano-quinolin-3-yl)amino-2-imidazoline.The above amine (45 mg, 0.24 mmol was mixed with 2-imidazolinesulfonicacid (72 mg, 0.48 mmol) in isobutyl alcohol (4 mL) and heated at refluxfor 3 days. The solvent was evaporated off to give a residue which wasdissolved in CHCl₃ and flash chromatographed over silica gel (18 g)eluting with EtOAc/MeOH/Et₃N (10:2:1) to afford an oil (28 mg, 66%yield). It was dissolved in EtOH and treated with fumaric acid (25 mg)in EtOH. Upon the addition of ether and refrigeration, the solution gavean off-white solid (22 mg): mp 183-185° C. (dec.). Anal. Calcd. forC₁₅H₂₀N₄·C₄H₄O₄ 1/4H₂O: C, 60.55; H, 6.55; N, 14.86. Found: C, 60.39; H,6.87; N, 14.64.

EXAMPLE 192-(6-Ethyl-5,6,7,8-tetrahydro-1,6-naphthyrid-3-yl)amino-2-imidazoline

6-Ethyl-5,6,7,8-tetrahydro-3-nitro-1,6-naphthyridine.1-Ethyl-4-piperidone (500 mg, 3.93 mmol) was mixed with1-methyl-3,5-dinitro-2-pyridone (392 mg, 1.97 mmol) in 1M methanolicammonia (40 mL, 40 mmol) and heated at reflux for 3 h. The solvent wasevaporated off and the residue was suspended in CHCl₃ and flashchromatographed over silica gel (32 g) eluting with EtOAc to afford anorange solid (379 mg, 93% yield).

3-Amino-6-ethyl-5,6,7,8-tetrahydro-7,6-naphthyridine. The above solid(185 mg, 0.89 mmol) was dissolved in conc. HCl (3 mL), cooled by an icewater bath and treated with tin (II, chloride dihydrate (600 mg, 2.66mmol) in conc. HCl (3 mL). The mixture was stirred at room temperaturefor 1 h before it was slowly poured into cold Na₂CO₃ solution.Extraction with CHCl₃/2-propanol (3:1) twice gave a light brown oil (114mg, 72% yield).

2-(6-Ethyl-5,6,7,8-tetrahydro-1,6-naphthyrid-3-yl)amino-2-imidazoline.The above amine (114 mg, 0.64 mmol) was mixed with 2-imidazolinesulfonicacid (193 mg, 1.29 mmol) in isobutyl alcohol (5 mL) and heated at refluxfor 2 days.

The solvent was evaporated off to give a residue which was dissolved inCHCl₃ and flash chromatographed over silica gel (19 g) eluting withEtOAc/MeOH/Et₃N (10:2:1) to afford a pale brown foam (75 mg, 48% yield).It was dissolved in EtOH and treated with fumaric acid (107 mg) in EtOH.The solvent was removed and the residue was recrystallized fromMeOH/ether to give an off-white solid (52 mg). Anal. Calcd. for C₁₃₁₉H₅·5/2C₄H₄O₄·1/3C₃H₈O 1/2H₂O: C, 51.06; H, 5.083; N, 12.41. Found: C,51.34; H, 5.77; N, 12.17.

EXAMPLE 20 2-(5,6,7,8-Tetrahydroquinolin-3-yl)amino-2-imidazoline

5,6,7,8tetrahydro-3-nitro-quinoline. A mixture of1-methyl-3,5-dinitro-2-pyridone(2.4 g, 0.012 mole), cyclohexanone (1.18g, 0.012 mole) and ammonia solution (2.0M, 120 mL) in methanol wasrefluxed overnight. The solvent was removed in vacuo and the residue wasdissolved in ethyl acetate. The soluble portion was flashchromatographed over silica gel (eluent: 90:10 v/v ethyl acetate-hexane)to give a yellow solid (2.02 g, 94% yield).

3-Amino-5,6,7,8-tetahydroquinoline. A solution of the above solid (0.541g, 3.0 mmole) in methanol (40 ml) was subjected to hydrogenation with aH₂ balloon in the presence of 10% palladium on carbon. The reaction wascarried out at room temperature overnight. The catalyst was thenfiltered off and the solvent was removed in vacuo to give a gray solid(0.44 g, 98% yield).

2-(5,6,7,8-Tetrahydroquinolin-3-yl)amino-2-imidazoline. A mixture of theabove solid (0.221 g, 1.49 mmole), 2-imidazoline-2-sulfonic acid (0.805g, 5.4 mmole) and isobutyl alcohol (4 mL) was refluxed for 18 hours. Thesolvent was removed in vacuo and the residue was flash chromatographedover silica gel (eluent: 10:2:1 v/v/v ethylacetate-methanol-triethylamine). The product was obtained in 100% yield(0.337 g) as a pale yellow solid. The above solid was treated in ethanolwith 1.0 equivalent of fumaric acid to give a fumarate as a white solid(59% yield): mp 201-203° C. Anal. Calcd. for C₁₂H₁₅N₄·1.5C₄H₄·0.5H₂O: C,54.13; H, 5.76; N, 14.04. Found: C, 54.04; H, 5.96; N, 13.69.

EXAMPLE 21 2-(2,3-Cyclopentenopyrid-5-yl)amino-2-imidazoline

2,3-Cyclopenteno-5-nitropyridine. A mixture of1-methyl-3,5-dinitro-2-pyridone (1.2 g, 6.0 mmole), cyclopentanone (0.5g, 6.0 mmole) and ammonia solution in methanol (2.0 M, 60 mL) wasrefluxed overnight. The solvent was removed in vacuo and the residue wasdissolved in ethyl acetate. The soluble portion was flashchromatographed over silica gel (eluent: 90:10 v/v ethylacetate-hexane). The product was obtained as a yellow solid (0.623 g,63% yield).

5-Amino-2,3-cyclopentenopyridine. A solution of the above solid (0.451g, 2.75 mmole) in methanol (40 mL) was subjected to hydrogenation with aH₂ balloon in the presence of 10% palladium on carbon. The reaction wascarried out at room temperature for 4 h. The catalyst was then filteredoff and the solvent was removed in vacuo to give a gray solid (0.36 g,98% yield).

2-(2,3-Cyclopentenopyrid-5-yl)amino-2-imidazoline. A mixture of theabove solid (0.18 g, 1.34 mmole), 2-imidazoline-2-sulfonic acid (0.70 g,4.67 mmole) and isobutyl alcohol (3 mL) was refluxed overnight. Thesolvent was removed in vacuo and the residue was flash chromatographedover silica gel (eluent: 10:2:1 v/v/v ethylacetate-methanol-triethylamine). The product was obtained in 92% yield(0.25 g) as a pale yellow solid. It was treated in ethanol with 1.2equivalents of fumaric acid to give a fumarate salt as a white solid(59% yield): mp 182.0-183.5° C. Anal. Calcd. for C₁₁H₁₄N₄1.5C₄H₄O₄·0.25H₂O: C 53.61; H 5.39; N 14.72. Found: C 53.47; H 5.70; N14.80.

EXAMPLE 222-(5,8-Methano-5,6,7,8-tetrahydroquinolin-3-yl)amino-2-imidazoline

5,6,7,8-Tetrahydro-5,8-methano-3-nitroquinoline. A mixture of1-methyl-3,5-dinitro-2-pyridone (0.8 g, 4.0 mmole), norcamphor (0.83 g,7.5 mmole) and ammonia solution in methanol (2.0 M, 40 mL) was refluxedfor 3 hours. The solvent was removed in vacuo and the residue wasdissolved in ethyl acetate. The soluble portion was flashchromatographed over silica gel (eluent: 85:15 v/v ethyl acetate-hexane)to give a yellow solid. It was recrystallized from ethyl acetate toafford yellow crystals (0.148 g, 21% yield).

3-Amino-5,6,7,8-Tetrahydro-5,8-methano-quinoline. A solution of theabove crystals (0.148 g, 0.84 mmole) in methanol (40 mL) was subjectedto hydrogenation with a H₂ balloon in the presence of 10% palladium oncarbon. The reaction was carried out at room temperature overnight. Thecatalyst was then filtered off and the solvent was removed in vacuo. Theproduct was obtained as a gray solid (0.059 g, 48% yield).

2-(5,8-Methano-5,6,7,8-tetrahydroquinolin-3-yl)amino-2-imidazoline. Amixture of the above solid (0.059 g, 0.40 mmole),2-imidazoline-2-sulfonic acid (0.25 g, 0.167 mmole) and isobutyl alcohol(3 mL) was refluxed overnight. The solvent was removed in vacuo and theresidue was flash chromatographed over silica gel (eluent: 10:2:1 v/v/vethyl acetate-methanol-triethylamine). The product was obtained in 80%yield (0.069 g) as a pale yellow solid. It was treated in isopropylalcohol with 1.0 equivalent of fumaric acid to give a fumarate salt as ayellow solid (44% yield): mp 164.0-166.0° C. Anal. Calcd. forC₂₂H₁₅N₄·1.5C₄H₄O₄·0.25H₂O: C, 56.09; H, 5.53; N, 13.78. Found: C,56.01; H, 5.47; N, 13.78.

EXAMPLE 232-(6-Benzyl-5,6,7,8-tetrahydro-1,6-naphthyrid-3-yl)amino-2-imidazoline

6-Benzyl-5,6,7,8-tetrahydro-3-nitro-1,6-naphthyridine. A mixture of1-methyl-3,5-dinitro-2-pyridone (1.2 g, 6.0 mmol), 1-benzyl-4-piperidone(1.12 g, 5.9 mmol) and ammonia solution in methanol (2.0 M, 60 mL) wasrefluxed for 3 h. The solvent was removed in vacuo and the residue wasdissolved in ethyl acetate. The soluble portion was flashchromatographed over silica gel (eluent: 90:10 v/v ethyl acetate-hexane)to give a yellow solid (0.79 g, 49.7% yield).

3-Amino-6-benzyl-5,6,7,8-tetrahydro-1,6-naphthyridine. A solution of theabove solid (0.79 g, 2.94 mmol) in methanol (100 mL was subjected tohydrogenation with a H₂ balloon in the presence of 10% palladium oncarbon. The reaction was carried out at room temperature overnight. Thecatalyst was then filtered off and the solvent was removed in vacuo. Theproduct was obtained as a gray solid (0.753 g, 100% yield).

2-(6-Benzyl-5,6,7,8-tetrahydro-1,6-naphthyrid-3-yl)amino-2-imidazoline.A mixture of the above solid (0.478 g, 2.0 mmol),2-imidazoline-2-sulfonic acid (0.9 g, 6.0 mmol) and isobutyl alcohol (3mL) was refluxed overnight. The solvent was removed in vacuo and theresidue was flash chromatographed over silica gel (eluent: 10:2:1 v/v/vethyl acetate-methanol-triethylamine). The product was obtained in 92%yield (0.565 g) as a pale yellow solid. It was treated in isopropylalcohol/diethyl ether with 2.0 equivalents of fumaric acid to give afumarate salt as a yellow solid (44% yield). Anal. Calcd. for C₁₈H₂₁N₅1.5C₄H₄O₄·1.5H₂O: C, 56.69; H, 5.91; N, 13.78. Found: C, 56.65; H, 5.77;N, 14.01.

EXAMPLE 24

2-(5,6,7,8-tetrahydro-6-oxa-quinolin-3-yl)amino-2-imidazoline

5,6,7,8-tetrahydro-3-nitro-6-oxa-quinoline. A mixture of1-methyl-3,5-dinitro-2-pyridone (0.8 g, 4 mmol),tetrahydro-4H-pyran-4-one (0.4 g, 4 mmol) and ammonia solution inmethanol (2.0 M, 40 mL) was refluxed for 4 h. The solvent was removed invacuo and the residue was dissolved in ethyl acetate. The solubleportion was flash chromatographed over silica gel (eluent: 90:10 v/vethyl acetate-hexane) to give a yellow solid (0.376 g, 52% yield).

3-Amino-5,6,7,8-tetrahydro-6-oxa-quinoline. A mixture of the above solid(0.37 g, 2.05 mmol), tin chloride dihydrate (1.17 g, 5.2 mmol) andhydrochloric acid (37% aqueous solution, 15 mL) was stirred at roomtemperature overnight and then neutralized with sodium hydroxidesolution to pH=8. The product was extracted with ethyl acetate. Theorganic phase was evaporated in vacuo to give a white solid 0.232 g, 75%yield).

2-(5,6,7,8-tetrahydro-6-oxa-quinolin-3-yl)amino-2-imidazoline. A mixtureof the above solid (0.232 g, 0.55 mmol), 2-imidazoline-2-sulfonic acid(0.7 g, 4.67 mmol) and isobutyl alcohol (3 mL) was refluxed for 3 days.The solvent was removed in vacuo and the residue was flashchromatographed over silica gel (eluent: 10:2:1 v/v/v ethylacetate-methanol-triethylamine). The product was obtained in 92.6% yield(0.312 g). It was treated in ethanol with 1.0 equivalent of fumaric acidto give a fumarate as a white crystal (47% yield): mp 201-202.5° C.Anal. Calcd. for C₁₁H₁₄N₄O·1.5C₄H₄O₄: C, 52.04; H, 5.10; N, 14.29.Found: C, 51.86; H, 5.12; N, 14.03.

EXAMPLE 252-(5,6,7,8-tetrahydro-6-thia-quinolin-3-yl)amino-2-imidazoline

5,6,7,8-tetrahydro-3-nitro-6-thia-quinoline. A mixture of1-methyl-3,5-dinitro-2-pyridone (0.6 g, 3.0 mmol),tetrahydrothiopyran-4-one (0.35 g, 3.0 mmol) and ammonia solution inmethanol (2.0 M, 30 mL) was refluxed for 6 h. The solvent was removed invacuo and the residue was dissolved in ethyl acetate. The solubleportion was flash chromatographed over silica gel (eluent: 90:10 v/vethyl acetate-hexane)to give a yellow solid (0.586 g, 99% yield).

3-Amino-5,6,7,8-tetrahydro-6-thia-quinoline. A mixture of the abovesolid (0.29 g, 1.48 mmol), tin chloride dihydrate (0.83 g, 3.68 mmol)and hydrochloric acid (37% aqueous solution, 15 mL) was stirred at roomtemperature overnight and then neutralized with sodium hydroxidesolution to pH=8. The product was extracted with ethyl acetate. Theorganic phase was concentrated in vacuo to give a white solid (0.200 g,81.6% yield).

2-(5,6,7,8-tetrahydro-6-thia-quinolin-3-yl)amino-2-imidazoline. Amixture of the above solid (0.200 g, 1.20 mmol),2-imidazoline-2-sulfonic acid (0.54 g, 3.6 mmol) and isobutyl alcohol (3mL) was refluxed for one day. The solvent was removed in vacuo and theresidue was column chromatographed over silica gel (eluent: 10:2:1 v/v/vethyl acetate-methanol-triethylamine). The product was obtained in 100%yield (0.313 g). It was treated in ethanol with 1.0 equivalent offumaric acid to give a fumarate salt as white crystals (50% yield): mp199.5-200.5° C. Anal. Calcd. for C₁₁H₁₄N₄S·1.5C₄H₄O₄: C, 50.00; H, 4.90;N, 13.73. Found: C, 49.85; H, 4.78; N, 13.58.

EXAMPLE 262-(5,6-Dihydro-7,7-Dimethyl-cyclopenta[b]cyrid-3-yl)amino-2-imidazoline

5,6-Dihydro-7,7-Dimethyl-3-nitro-cyclopenta[b]pyridine. A mixture of1-methyl-3,5-dinitro-2-pyridone (0.8 g, 4.0 mmol),2,2-dimethyl-cyclopentanone (0.45 g, 4.0 mmol) and ammonia solution (2.0M) in methanol (40 mL) was refluxed overnight. The solvent was removedin vacuo and the residue was dissolved in ethyl acetate. The solubleportion was flash chromatographed over silica gel (eluent: 90:10 v/vethyl acetate-hexane) to give a yellow solid (0.183 g, 24% yield).

3-Amino-5,6-dihydro-7,7-Dimethyl-cyclopenta[b]pyridine. A solution ofthe above solid (0.183 g, 0.95 mmol) in methanol (40 mL) was subjectedto hydrogenation with a H₂ balloon in the presence of 10 palladium oncarbon. The reaction was carried out at room temperature overnight. Thecatalyst was then filtered off and the solvent was removed in vacuo. Theproduct was obtained in 100% yield.

2-(5,6-Dihydro-7,7-Dimethyl-cyclopenta[b]pyrid-3-yl)amino-2-imidazoline.A mixture of the above intermediate (0.154 g, 0.95 mmol),2-imidazoline-2-sulfonic acid (0.40 g, 2.67 mmol) and isobutyl alcohol(3 mL) was refluxed overnight. The solvent was removed in vacuo and theresidue was flash chromatographed over silica gel (eluent: 10:2:1 v/v/vethyl acetate-methanol-triethylamine). The product was obtained in 47%yield (0.103 g). It was treated in ethanol with 2 equivalents of fumaricacid to give a fumarate salt as a yellow solid (34% yield): mp191.5-193° C. Anal. Calcd. for C₁₃H₁₈N₄·1.5C₄H₄O₄0.2H₂O: C, 55.93; H,6.03; N, 13.73. Found: C, 56.26; H, 6.41; N, 13.39.

EXAMPLE 27 2-(2,3-Cyclopenteno-1-oxido-5-pyridyl)amino-2-imidazoline

A mixture of 2-(2,3-Cyclopentenopyrid-5-yl)amino-2-imidazoline (0.1 g,0.5 mmol), hydrogen peroxide (30% aqueous solution, 0.1 mL) and aceticacid (5 mL) was heated at 90-100° C. for 10 h. Another 0.1 mL ofhydrogen peroxide was added. The reaction was complete after heating at90-100° C. overnight. The solvent was removed in vacuo and the residuewas flash chromatographed over silica gel (eluent: 10:2:1 v/v/v ethylacetate-methanol-triethylamine). The product was obtained in 95% yield(0.102 g). It was treated in ethanol with one equivalent of fumaric acidto give a fumarate salt as a white solid (54% yield). Anal. Calcd. forC₁₁H₂₄N₄O·1.2C₄H₄O₄: C, 53.08; H, 5.30; N, 15.67. Found: C, 52.87; H,5.16; N, 15.89.

EXAMPLE 28 2-(2-Bromo-5,6-cyclopenteno-3-pyridyl)amino-2-imidazoline

A mixture of 2-(2,3-Cyclopentenopyrid-5-yl)amino-2-imidazoline (0.12 g,0.59 mmol), bromine (0.4 mL) and acetic acid (3 mL) was stirred at roomtemperature overnight. The acetic acid was then removed in vacuo and theresidue was basified with an ammonia solution (2.0 M) in methanol topH=8. The solvent was evaporated. The product was separated by flashchromatography (eluent: 10:2:1 v/v/v ethylacetate-methanol-triethylamine) to give the product in 36% yield (0.060g). It was treated in ethanol with 2 equivalents of fumaric acid to givea fumarate salt as a white solid (79% yield): mp 234-235° C. Anal.Calcd. for C₁₁H₁₃BrN₄·0.65C₄H₄·0.33C₂H₆O: C, 46.06; H, 4.76; N. 15.08.Found: C, 45.85; H, 4.71; N, 15.07.

EXAMPLE 29 2-(2,4-Dibromo-5,6-cyclopentenopyrid-3-yl)amino-2-imidazoline

3-Amino-2,4-Dibromo-5,6-cyclopentenopyridine. A mixture of5-amino-2,3-cyclopentenopyridine (0.12 g, 0.9 mmol), bromine (0.2 mL)and acetic acid (10 mL) was stirred at room temperature for 2 h. Theacetic acid was removed in vacuo. The product was separated by flashchromatography (eluent: 80:20 v/v hexane-ethyl acetate) to give a whitesolid (0.12 g, 46%yield).

1-Acetyl-2-(2,4-Dibromo-5,6-cyclopentenopyrid-3-yl)amino-2-imidazoline.A mixture of the above solid (0.183 g, 0.63 mmol),N-acetyl-2-imidazolidone (0.1 g, 0.78 mmol) and phosphorus oxychloride(5 mL) was heated at about 55° C. overnight. The reaction solution wasneutralized with saturated aqueous solution of sodium bicarbonate andthen extracted with ethyl acetate. The organic phase was concentratedunder reduced pressure. The solid residue was recrystallized frommethanol/ethyl acetate to give a white solid (0.135 g, 54% yield).

2-(2,4-Dibromo-5,6-cyclopentenopyrid-3-yl)amino-2-imidazoline. A mixtureof the above solid (0.135 g, 0.34 mmol) and saturated hydrogen chloridesolution in ethanol (5 mL) was first stirred at room temperatureovernight and then heated at 50° C. for 6 h. The solvent was evaporatedand the residue was recrystallized from ethanol to give a hydrochloridesalt as a light brown solid (0.028 g): mp 191-194° C. Anal. Calcd. forC₂₂H₁₂Br₂N₄HCl: C, 33.29; H, 3.27; N, 14.12. Found: C, 33.04; H, 3.66;N, 13.75. The supernatant was basified with 2.0 M ammonia solution inmethanol and evaporated to dryness. The residue was purified by flashchromatography (eluent: 10:2:1 v/v/v ethylacetate-methanol-triethylamine) to give another 0.106 g of product asthe free base. Total yield: 100%.

EXAMPLE 302-(5,6-Cyclopenteno-2,4-dimethyl-pyrid-3-yl)amino-2-imidazoline

3-Amino-5,6-cyclopenteno-2,4-dimethylpyridine. To a dry pressure tubewas added 3-Amino-2,4-Dibromo-5,6-cyclopentenopyridine (0.4 g, 1.37mmol), tetramethyltin (0.56 mL, 4.0 mmol), anhydrous DMF (6 mL) and acatalytic amount of bis (triphenylphosphine) palladium(II) chloride. Thetube was sealed under Argon protection, wrapped with aluminum foil andheated at 120°-140° C. overnight. The solvent was then removed in vacuoand the residue was flash chromatographed over silica gel (eluent:10:2:1 v/v/v ethyl acetate-methanol-triethylamine) to give the product(0.219 g, 99% yield).

2-(5,6-Cyclopenteno-2,4-dimethyl-pyrid-3-yl)amino-2-imidazoline. To amixture of the above intermediate (0.2 g, 1.23 mmol), sodium bicarbonate(1 g), chloroform (8 mL) and water (6 mL) was added thiophosgene (1 mL).The solution was vigorously stirred at room temperature overnight andbasified to pH 8 with saturated sodium bicarbonate solution. The organiclayer was separated and concentrated to give a residue (0.261 g, 100%yield). A portion (0.25 g, 1.23 mmol) was mixed with ethylenediamine (1mL) and methanol (10 mL), and was stirred at room temperature for 2 h.The solvent was then removed in vacuo and the residue was subjected toflash chromatography over silica gel (eluent: 100:20 v/v ethylacetate-2.0 M ammonia solution in methanol). The desired intermediatewas thus obtained in 97% yield (0.309 g). This intermediate (0.309 g,1.17 mmol) was dissolved in acetonitrile (5 mL) and stirred at 0° C. inthe presence of 2-chloro-3-ethylbenzoxazolium tetrafluoroborate (0.38 g)for 4 h. Triethylamine (0.2 mL) was then added. The mixture was stirredfor another 3 h. The solvent was removed in vacuo and the residue waspurified by flash chromatography (eluent: 10:2:1 v/v/v ethylacetate-methanol-triethylamine) to give the product in 46% yield (0.123g). It was treated in ethanol with 2 equivalents of fumaric acid to givea fumarate salt as a white solid (53% yield): mp 220-221° C. Anal.Calcd. for C₁₃H₁₉N₄·1.5C₄H₄O₄: C, 56.43; H, 5.98; N, 13.85. Found: C,56.41; H, 6.13; N, 13.85.

EXAMPLE 31 2-(5,6-Cyclopenteno-2,4-diethyl-3-pyridyl)amino-2-imidazoline

3-Amino-5,6-cyclopenteno-2,4-diethylpyridine. To a dry pressure tube wasadded 3-Amino-2,4-Dibromo-5,6-cyclopentenopyridine (0.4 g, 1.37 mmol),tetraethyltin (0.8 mL, 4.0 mmol), anhydrous DMF (6 mL) and a catalyticamount of bis(triphenylphosphine) palladium(II) chloride. The tube wassealed under Argon protection, wrapped with aluminum foil and heated at120°-140° C. overnight. The solvent was then removed in vacuo and theresidue was flash chromatographed over silica gel (eluent: 10:2:1 v/v/vethyl acetate-methanol-triethylamine) to give the product in 82% yield(0.212 g).

2-(5,6-Cyclopenteno-2,4-diethyl-3-pyridyl)amino-2-imidazoline. To amixture of the above intermediate (0.126 g, 0.66 mmol), sodiumbicarbonate (0.5 g), chloroform (5 mL) and water (5 mL) was addedthiophosgene (0.8 mL). The solution was vigorously stirred at roomtemperature overnight and basified to pH 8 with saturated sodiumbicarbonate solution. The organic layer was separated and concentratedto give a residue (0.180 g, 100% yield). A portion (0.154 g, 0.66 mmol)was mixed with ethylenediamine (0.44 mL) and methanol (10 mL), and wasstirred at room temperature for 2 h. The solvent was then removed invacuo and the residue was subjected to flash chromatography over silicagel (eluent: 10:2:1 v/v/v ethyl acetate-methanol-triethylamine) to givethe desired intermediate in 92% yield (0.178 g). A solution of theintermediate (0.178 g, 0.61 mmol) in acetonitrile (5 mL) was stirred at0° C. in the presence of 2-chloro-3-ethylbenzoxazolium tetrafluoroborate(0.19 g) for 4 h. Triethylamine (0.2 mL) was then added. The mixture wasstirred for another 3 h. The solvent was removed in vacuo and theresidue was purified by flash chromatography (eluent: 10:2:1 v/v/v ethylacetate-methanol-triethylamine) to give the product in 44% yield (0.070g).

EXAMPLE 32 4-(4,5-Dihydro-1H-imidazol-4-ylmethyl)-quinoline fumarate

Step A.

2-(Benzhydrylideneamino)-3-quinolin-4-yl-propionitrile. ToN-(Diphenylmethylene) aminoacetonitrile (0.360 g, 1.633 mmol) in 10 mlof anhydrous THF and HMPA (hexamethyl phosphoramidite) (0.38 ml, 2.12mmol), at −78° C., LDA (2.0 M, 1.06 ml, 2.12 mmol) was added dropwiseover a period of 5 minutes. The color of solution turns from colorlessto yellow to dark brown. It was then stirred at −78° C. for one hour.4-Chloromethylquinoline (0.29 g, 1.63 mmol) was added dropwise over aperiod of 5 minutes and the reaction mixture was slowly brought to roomtemperature over a period of five minutes. The reaction mixture wasquenched by addition of ice and partitioned between EtOAc (20 ml) andwater (5 ml). The organic layer was dried over sodium sulfate, filteredconcentrated and column purified (hexanes:EtOAc; 3.5:1.5) to give 0.155g (26%) of the product as a syrup, which was used as such for thesubsequent step.

Step B.

2-Amino-3-quinolin-4-yl-propionitrile. To2-(Benzhydrylideneamino)-3-quinolin-4-yl-propionitrile (0.155 g, 4.29mmol) in 5 ml dioxane, 1N HCl (1.3 ml, 12.8 mmol) was added and thereaction mixture stirred at room temperature overnight. The solution wasconcentrated under reduced pressure, partitioned between 10 ml water andEtOAc (10 ml). The organic layer was dried over sodium sulfate filteredand concentrated to give 2-Amino-3-quinolin-4-yl-propionitrile 0.036 g(43%) which was used as such for the subsequent step.

Step C.

3-Quinolin-4-yl-propane-1,2-diamine. To2-Amino-3-quinolin-4-yl-propionitrile (0.036 g, 0.18 mmol in 10 ml ofethanol, ammonia gas was bubbled for 15 minutes. 1 g of Raney Ni (washedwith 2×50 ml water and 2×50 ml ethanol) was added to the solution andthe reaction mixture was hydrogenated at 50 psi for 2 hours. Thereaction mixture was filtered over celite and concentrated to give 0.250g (50%) of the product which was used as such for the subsequent step.

Step D.

4-(4,5-Dihydro-1H-imidazol-4-ylmethyl)-quinoline. To3-Quinolin-4-yl-propane-1,2-diamine (0.080 g, 3.98 mmol) in 5 ml of drydichloromethane, formidic acid ethyl ester hydrochloride (0.174 g, 7.96mmol) (Ohme, R. et al. Angew. Chem. Int. Engl. Ed. 1967, 6, 90) wasadded. The reaction mixture was stirred overnight at room temperature.Aqueous ammonia (2 ml) was added to the reaction mixture and waspartitioned between EtOAc (2×5 ml) and water. The organic layer wasdried, filtered and concentrated to give 0.084 g (100%) of the productas a syrup.

Step E.

4-(4,5-Dihydro-1H-Imidazol-4-ylmethyl)-quinoline fumarate. To4-(4,5-Dihydro-1H-imidazol-4-ylmethyl)-quinoline (0.76 g, 0.359 mmol) in5 ml ethanol, fumaric acid (0.041 g, 0.359 mmol) was added and thesolution was heated till all the fumaric acid dissolves. The reacticmixture was concentrated to yield 0.077 (100%) of a solid which wasrecrystallized from isopropanol: m.p. 180-182° C.; Anal. Calcd. forC₁₃H₁₃N₃ 1.5 fumaric acid. 0.1 H₂O: C, 58.94; H, 5.00; N, 10.85. Found:C, 58.99; H, 5.03; N, 10.84.

EXAMPLE 33 4-[1-(1H-Imidazol-4-yl)-ethyl]-quinoline dihydrochloride

Step A.

1-Quinolin-4-yl-ethanol. To 4-quinolinecarbaldehyde (2 g, 12.73 mmol) in20 ml anhydrous ether, MeLi (1.4M, 10 ml, 13.9 mmol) was added dropwiseover a period of five minutes at 0° C. The reaction mixture was stirredat room temperature for 3 hours. The solution was partitioned betweenether (20 ml) and water (10 ml). The organic layer was dried over sodiumsulfate, filtered and concentrated to give 1.43 g (59%) of the productwhich was then used as such for the subsequent step.

Step B.

4-(1-Chloroethyl)-quinoline. To 1-Quinolin-4-yl-ethanol (1.4 g, 8.09mmol) in 15 ml chloroform, thionyl chloride (1.8 ml, 20.2 mmol) wasadded dropwise over a five minute period at room temperature. Stirringwas continued for 30 minutes after which the reaction mixture was cooledto 0° C. and quenched carefully by the addition of saturated aqueousNaHCO₃ (20 ml). The chloroform layer was dried over sodium sulfate,filtered and concentrated. Column purification (hexane:ethyl acetate;1.5:3.5) gave 1.54 g (100%) of the product as a syrup which was used assuch for the subsequent step.

Step C.

2-(Benzhydrylideneamino)-3-quinolin-4-yl-butyronltrile. ToN-(Diphenylmethylene) aminoacetonitrile (2.26 g, 10.2 mmol) in 10 ml ofanhydrous THF and HMPA (2.15 ml, 12.14 mmol), at −78° C., LDA (2.0 M,6.0 ml, 12.14 mmol was added dropwise over a period of 5 minutes. Thecolor of solution turns from colorless to yellow to dark brown. It wasthen stirred at −78° C. for one hour. Then 4-(1-Chloroethyl)-quinoline(1.79 g, 9.34 mmol) was added dropwise and the reaction mixture wasslowly brought to room temperature over a period of five minutes,quenched by addition of ice and partitioned between EtOAc (20 ml) andwater (5 ml). The organic layer was dried over sodium sulfate, filtered,concentrated and column purified (hexanes:EtOAc; 3.5:1.5) to give 3.0 g(86%) of the product as a syrup which was used as such for thesubsequent step.

Step D.

2-Amino-3-quinolin-4-yl-butyronitrile. To2-(Benzhydrylideneamino)-3-quinolin-4-yl-butyronitrile (3.0 g, 7.3 mmol)in 30 ml dioxane, 1N HCl (30 ml, 29.99 mmol, was added and the reactionmixture stirred at room temperature overnight. The solution was thenconcentrated under reduced pressure, partitioned between water (10 ml)and EtOAc (10 ml). The organic layer was dried over sodium sulfate,filtered and concentrated to give 1.58 g (88%) of the product which wasused as such for the subsequent step.

Step E.

3-Quinolin-4-yl-butane-1,2-diamine. To2-Amino-3-quinolin-4-yl-butyronitrile (1.58 g, 6.42 mmol) in 10 ml ofethanol, ammonia gas was bubbled for 15 minutes. 2 g of Raney Ni (washedwith 2×50 ml water and 2×50 ml ethanol) was added to the solution andthe reaction mixture was hydrogenated at 50 psi for 2 hours, filteredover celite and concentrated to give 1.54 g (96%) of the product whichwas then used as such for the subsequent step.

Step F.

4-[1-(4,5-Dihydro-1H-imidazol-4-yl)-ethyl]quinoline. To3-Quinolin-4-yl-butane-1,2-diamine (1.54 g, 7.16 mmol) in 5 ml ofdichloromethane, formidic acid ethyl ester hydrochloride (1.57 g, 14.3mmol) was added. The reaction mixture was stirred overnight at roomtemperature. Aqueous ammonia (2 ml) was added to the reaction mixtureand was partitioned between EtOAc (2×5 ml) and water. The organic layerwas dried, filtered and concentrated to give 1.16 g (73%) of the productas a syrup which was used for the subsequent step.

Step G.

4-[1-(1H-Imidazol-4-yl)-ethyl]-quinoline. To oxalyl chloride (0.85 μl,0.976 mmol) in 5 ml of anhydrous dichloromethane at −78° C.,dimethylsulfoxide (0.14 ml, 1.95 mmol) was added over a five minuteperiod. After stirring for 5 minutes at the same temperature,4-[1-(4,5-Dihydro-1H-imidazol-4-yl)-ethyl]quinoline (0.200 g, 0.888mmol) was added slowly and the reaction mixture was stirred for afurther 20 minutes at −78°. Triethylamine (0.62 ml, 4.44 mmol) was addedand the reaction mixture was stirred for 5 minutes at −78° C. and then20 minutes at room temperature. The reaction mixture was concentratedunder reduced pressure and partitioned between EtOAc (10 ml) and water(5 ml). The organic layer was dried over sodium sulfate, filtered,concentrated and column purified [EtOAc:MeOH:Methanol NH₃ (1.0 M);3.5:1:0.5) to give 0.100 g (51%) of the product as a syrup.

Step H.

4-[1-(1H-Imidazol-4-yl)-ethyl]-quinoline dihydrochloride. To4-[1-(1H-Imidazol-4-yl)-ethyl]-quinoline (0.067, 0.300 mmol) in 5 mlmethanol, 3 ml of HCl in dioxane was added and the reaction mixture wasconcentrated under reduced pressure to give 0.0.067 g, (100%) of theproduct as a pale yellow solid which was recrystallized fromisopropanol: m.p. 276-278° C.; Anal. Calcd. for C₁₄H₁₅N₃Cl₂ 0.6 moleH₂O: C, 54.77; H, 5.32; N, 13.69. Found: C, 54.93; H, 4.94; N, 13.28.

EXAMPLE 34 4-[-1-(1H-Imidazol-4-yl)-propyl]-quinoline dihydrochioride

Step A. 4-[1-(1H-Imidazol-4-yl)-propyl]-quinoline. This compound wasprepared starting from 4-quinolinecarboxaldehyde using experimentalconditions outlined for example 33, except for substituting MeLi in stepA with EtMgBr.

Step B. 4-[1-(1H-Imidazol-4-yl)-propyl]-quinoline dihydrochloride. To4-[1-(1H-Imidazol-4-yl)-propyl]-quinoline (0.185, 0.779 mmol) in 5 mlmethanol, 3 ml of HCl in dioxane was added and the reaction mixture wasconcentrated under reduced pressure to give 0.240 g, (100% of theproduct as a foam.

EXAMPLE 35 4-[1-(1H-Imidazol-4-yl)-ethyl]-2-methyl-quinolinedihydrochloride

Step A. 4-[1-(1H-Imidazol-4-yl)-ethyl]-2-methyl-quinoline. This compoundwas prepared starting from 2-Methyl-4-quinolinecarbaldehyde (Minisci, F.et al. J. Org. Chem. 1986, 51, 536) and using experimental conditionsoutlined for example 33.

Step B. 4-[1-(1H-Imidazol-4-yl)-ethyl]-2-methyl-quinolinedihydrochloride. To 4-[1-(1H-Imidazol-4-yl)-ethyl]-2-methyl-quinoline(0.062, 0.261 mmol) in 5 ml methanol, 3 ml of HCl in dioxane was addedand the reaction mixture was concentrated under reduced pressure to give0.080 g, (100%; of the product as a pale yellow solid which wascrystallized from isopropanol-ether: m. 238-240° C.; Anal. Calcd. forC₁₅H₁₇N₃Cl₂ 1.0 mole H₂O: C, 54.86; H, 5.82. Found: C, 54.83; H, 5.99.

EXAMPLE 36 4-[1-(1H-Imidazol-4-yl)-ethyl]-2-phenyl-quinolinedihydrochloride

Step A. 1-(2-phenylquinolin-4-yl)-ethanone. To methyl2-phenyl-4-quinolinecarboxylate (1 g, 3.80 mmol) in 10 ml ether, at 0°was added MeLi (1.4M, 3.0 ml, 4.1 mmol) dropwise over a five minuteperiod. The reaction mixture was stirred at 0° C. for 3 minutes andquenched by addition of 10 ml of water. The ether layer was separated,dried over sodium sulfate, filtered, concentrated and column purified(hexane:EtOAc; 4.5:0.5) to give 0.233 g (23%) of the product as a syrupwhich was used as such for the subsequent step.

Step B.

1-(2-phenylquinolin-4-yl)-ethanol. To 1-(2-phenylquinolin-4-yl)-ethanone(0.233 g, 0.943 mmol) in 5 ml methanol, at room temperature sodiumborohydride (0.036 g, 0.943 mmol) was added and the solution stirred for30 minutes. The reaction mixture was concentrated and partitionedbetween EtOAc (10 ml) and water (5 ml). The organic layer was dried oversodium sulfate, filtered, concentrated and column purified(hexane:EtOAc; 3.5:1.5) to give 0.145 g (62%) of the product as a syrupwhich was used as such for the subsequent step.

Step C.

4-[1-(1H-Imidazol-4-yl)-ethyl]-2-phenyl-quinoline. This compound wasprepared starting from 1-(2-phenylquinolin-4-yl)-ethanol (step B) andfollowing experimental conditions outlined for example 33.

Step D.

4-[1-(1H-Imidazol-4-yl)-ethyl]-2-phenyl-quinoline dihydrochloride. To4-[1-(1H-Imidazol-4-yl)-ethyl]-2-phenyl-quinoline (0.02 g, 0.066 mmol)in 5 ml methanol, 3 ml of HCl in dioxane was added and the reactionmixture was concentrated under reduced pressure to give 0.025 g, (100%)of the product as a pale yellow solid which was crystallized fromisopropanol-ethyl acetate: m.p. 175-180° C.; Anal. Calcd. forC₂₃H₁₅N₃Cl₂ 1.0 mole H₂O: C, 64.52; H, 5.14; N, 11.29. Found: C, 64.83;H, 5.59; N, 11.23.

EXAMPLE 37 4-[1-(1H-Imidazol-4-yl)-ethyl]-isoquinoline dihydrochloride

Step A.

4-[1-(1H-Imidazol-4-yl)-ethyl]-isoquinoline. This compound was preparedstarting from Isoquinoline-4-carbaldehyde (Minisci, F. et al. J. Org.Chem. 1986, 51, 536) and using experimental conditions outlined forexample 33.

Step B.

4-[1-(1H-Imidazol-4-yl)-ethyl]-isoquinoline dihydrochloride. To4-[1-(1H-Imidazol-4-yl)-ethyl]-isoquinoline (0.105, 0.470 mmol) in 5 mlmethanol, 3 ml of HCl in dioxane was added and the reaction mixture wasconcentrated under reduced pressure to give 0.105 g, (866) of theproduct as a brown solid which was crystallized from isopropanol: m.p.185-190° C.; Anal. Calcd. for C₁₄H₁₅N₃Cl₂ 0.9 mole H₂O: C, 53.82; H,5.42; N, 13.45. Found: C, 54.01; H, 5.77; N, 13.98.

EXAMPLE 38 4-[1-(1H-Imidazol-4-yl)-propyl]-isoquinoline dihydrochloride

Step A.

4-[1-(1H-Imidazol-4-yl)-propyl]-isoquinoline. This compound was preparedstarting from Isoquinoline-4-carbaldehyde and using experimentalconditions outlined for example 33 except for substituting MeLi in stepA with EtMgBr.

Step B.

4-[1-(1H-Imidazol-4-yl)-propyl]-isoquinoline dihydrochloride. To4-1-(1H-Imidazol-4-yl)-propyl]-isoquinoline (0.077 g, 0.324 mmol) in 5ml methanol, 3 ml of HCl in dioxane was added and the reaction mixturewas concentrated under reduced pressure to give 0.086 g, (86%) of theproduct as a yellow solid which was crystallized from isopropanol-ether:m.p. 173-176° C.; Anal. Calcd. for C₁₃H₁₇Cl₂ 0.6 mole dioxane: C, 55.39;Hz, 5.70, N. 11.54 Found: C, 55.85; H, 6.09; N, 11.15.

EXAMPLE 39 (1H-Imidazol-4-yl)-quinolin-4-yl-methanol dihydrochloride

Step A.

2-(tert-Butyldimethylsilyl)-4-(hydroxyquinolin-4-yl-methyl)-imidazole-1-sulfonicacid dimethylamide. To N,N-dimethylsulfamoyl-2-(tert-butyldimethylsilyl)imidazole (3.165 g, 1.05 mmol) (Chadwick, D. J. et al. J. Chem. Soc.Perkin Trans. I. 1984, 481) in 8 ml THF, n-BuLi (0.55 ml, 1.1 mmol) wasadded over a period of 5 minutes at −78° C. and the reaction mixture wasstirred for 30 minutes at the same temperature. 4-quinolinecarbaldehyde(0.165 g, 1.05 mmol) was added neat to the solution and the reactionmixture was stirred for 10 minutes at −78° C. and then at roomtemperature for 30 minutes. The reaction mixture was partitioned betweenEtOAc (50 ml) and water (10 ml). The organic layer was dried over sodiumsulfate, filtered and concentrated to yield 0.462 g (100%) of theproduct.

Step B.

(1H-Imidazol-4-yl)-quinolin-4-yl-methanol. To(1H-Imidazol-4-yl)-quinolin-4-yl-methanol (0.150 g, 0.32 mmol), 7 ml of1.5N HCl was added and the contents refluxed for 2 hours. The reactionmixture was concentrated, partitioned between water (10 ml) and EtOAc(2×10 ml). The organic layer was dried over sodium sulfate, filtered,concentrated and column purified (CH₂Cl₂: MeOH: Methanol-NH, (1.0M)(4.5:0.25:0.25) to yield 0.072 g (100%) of the product.

Step C.

(1H-Imidazol-4-yl)-quinolin-4-yl-methanol dihydrochloride. To(1H-Imidazol-4-yl)-quinolin-4-yl-methanol (0.030 g, 0.133 mmol) in 5 mlmethanol, 3 ml of HCl in dioxane was added and the reaction mixture wasconcentrated under reduced pressure to give 0.033 g, (85%) of theproduct as a solid: m.p. 200-202° C.; Anal. Calcd. for C₂₃H₁₃N₃OCl₂ 1.0H₂O: C, 49.38; Hz, 4.78; N, 13.29. Found: C, 49.52; H 4.72; N 13.52.

EXAMPLE 40 4-[(1H-Imidazol-4-yl)-methoxymethyl]quinoline dihydrochloride

Step A.

2-(tert-Butyldimethylsilyl)-4-(methoxyquinoline-4-yl-methyl)-imidazole-1-sulfonicacid dimethylamide. To pentane washed sodium hydride (0.048 g, 1.2 mmol)in 5 ml of THF at 0° C.,2-(tert-Butyldimethylsilyl)-4-(hydroxyquinolin-4-yl-methyl)-imidazole-1-sulfonicacid dimethylamide (example 8, step A) (0.375 g, 0.811 mmol) was addedslowly over a period of 5 minutes. After stirring at room temperaturefor 15 minutes, it was again cooled to 0° C. and methyl iodide (0.1 ml,1.62 mmol) was added neat. The reaction mixture was stirred at roomtemperature for 1 hour, concentrated under reduced pressure andpartitioned between EtOAc (10 ml) and water (10 ml). The organic layerwas dried over sodium sulfate, filtered and concentrated to yield 0.32 g(83%) of the product as a syrup.

Step B.

4-[(1H-Imidazol-4-yl)-methoxymethyl]quinoline. To2-(tert-Butyldimethylsilyl)-4-(methoxyquinolin-4-yl-methyl)-imidazole-1-sulfonicacid dimethylamide. (0.32 g, 0.672 mmol), 7 ml of 1.5N HCl was added andthe solution refluxed for two hours. The reaction mixture wasconcentrated, partitioned between water(10 ml) and EtOAc (2×10 ml). Theorganic layer was dried over sodium sulfate, filtered, concentrated andcolumn purified (CH₂Cl₂: MeOH: methanol-NH-₂ (1.0 M); (4.5:0.25:0.25) toyield 0.160 g (100%) of the product as a syrup.

Step C.

4-[(1H-Imidazol-4-yl)-methoxymethyl]quinoline dihydrochloride. To4-[(1H-Imidazol-4-yl)-methoxymethyl]quinoline (0.150 g, 0.66 mmol) in 5ml methanol, 3 ml of HCl in dioxane was added and the reaction mixturewas concentrated under reduced pressure to give 0.116 g, (80%) of theproduct as a white solid: m.p. 188-190° C.; Anal. Calcd. forC₁₄H₁₅N₃OCl₂ 0.6 mole H₂O: C, 52.06; H; 5.06. Found: C, 52.18; H; 5.40.

EXAMPLE 41 4-(1H-Imidazol-4-yl-methyl)-quinoline dihydrochloride

Step A.

Aceticacid-[2-(tert-Butyldimethylsilyl))-1-dimethylsulfamoyl-1H-imidazol-4-yl]-quinolin-4-yl-methylester. To2-(tert-Butyldimethylsilyl)-4-(hydroxyquinolin-4-yl-methyl)-imidazole-1-sulfonicacid dimethylamide (example 8, step A) (0.750 g, 1.62 mmol) in 8 ml ofanhydrous toluene at 0° C., pyridine (0.16 ml, 1.94 mmol) was addedfollowed by acetyl chloride (0.14 ml, 1.94 mmol). The solution wasstirred at room temperature for two hours. It was cooled to 0° C. andice cubes were added. The reaction mixture was partitioned betweentoluene (5 ml) and water (5 ml). The organic layer was dried over sodiumsulfate, filtered, concentrated under reduced pressure and columnpurifies (hexanes:EtOAc; 1:4) to give 0.84 g (100%) of the product.

Step B.

4-Quinolin-4-yl-methyl-imidazole-1-sulfonic acid dimethylamide. ToAceticacid-[2-(tert-Butyldimethylsilyl)-1-dimethylsulfamoyl-1H-imidazol-4-yl]-quinolin-4-yl-methylester (0.895 g, 1.72 mmol) in 10 ml of ethanol, 0.3 g of palladium oncarbon (10%) was added and the solution hydrogenated at 40 psi for 18hours. The solution was filtered over celite and concentrated underreduced pressure to give 0.190 g (53%) of the product as a syrup.

Step C.

4-(1H-Imidazol-4-yl-methyl)-quinoline. To4-Quinolin-4-yl-methyl-imidazole-1-sulfonic acid dimethylamide 0.16 g,0.765 mmol), 7 ml of 1.5N HCl was added and the solution refluxed fortwo hours. The reaction mixture was concentrated, partitioned betweenwater (10 ml) and EtOAc (2×10 ml). The organic layer was dried oversodium sulfate, filtered, concentrated and column purified (CH₂Cl₂:MeOH:methanol-NH₃ (1.0M) ; (4.5:0.25:0.25) to yield 0.080 g (51% of theproduct as a syrup.

Step D.

4-(1H-imidazol-4-yl-methyl)-quinoline dihydrochloride. To4-(1H-Imidazol-4-yl-methyl)-quinoline (0.08 g, 0.382 mmol) in 5 mlmethanol, 3 ml of HCl in dioxane was added and the reaction mixture wasconcentrated under reduced pressure to give 0.107 g, (100%) of theproduct as a solid: m.p. >300° C.; Anal. Calcd. for C₁₃H₂₃N₃Cl1.0 moleH₂O: C, 52.02; H, 5.04; N 14.00. Found: C, 52.00; H, 4.81; N, 14.04.

EXAMPLE 42 4-(1H-Imidazol-4-yl-methyl)-isoquinoline dihydrochloride

Step A.

2-(tert-Butyldimethylsilyl)-4-(hydroxyisoquinolin-4-yl-methyl)-imidazole-1-sulfonicacid dimethylamide. This compound was prepared according to experimentalconditions outlined in example 39, step A, starting withisoquinoline-4-carbaldehyde (Gilman, H. et al. J. Org. Chem. 1957, 22,565.) and N,N-dimethylsulfamoyl-2-(tert-butyldimethylsilyl)imidazole(Chadwick, D. J. et al. J. Chem. Soc. Perkin Trans. I. 1984, 481).

Step B.

2-(tert-Butyldimethylsilyl)-4-(chloroisoquinolin-4-yl-methyl)-imidazole-1-sulfonicacid dimethylamide. This compound was prepared from2-(tert-Butyldimethylsilyl)-4-(hydroxyisoquinolin-4-yl-methyl)-imidazole-1-sulfonicacid dimethylamide following experimental conditions outlined in example33, step B.

Step C.

4-Isoquinolin-4-yl-methyl-imidazole-1-sulfonic acid dimethyl amide. To2-(tert-Butyldimethylsilyl)-4-(chloroisoquinolin-4-yl-methyl)-imidazole-1-sulfonicacid dimethylamide (0.150 g, 0.312 mmol) in 0.6 ml acetic acid (0.5mmol), zinc dust (0.300 g, 5.55 mmol) was added and the solution stirredfor 24 hours at room temperature. It was neutralized with ammoniumhydroxide, EtOAc (20 ml) was added to the solution and filtered. Thefiltrate was partitioned between ethyl acetate and water (10 ml). Theorganic layer was dried over sodium sulfate, filtered and concentrated.Purification by column chromatography (EtOAc:MeOH; 4:1) gave 0.075 g(74%) of the product as a syrup.

Step D.

4-(1H-Imidazol-4-yl-methyl)-isoquinoline. To4-Isoquinolin-4-yl-methyl-imidazole-1-sulfonic acid dimethyl amide(0.110 g, 0.312 mmol), 7 ml of 1.5N HCl was added and the solutionrefluxed for two hours. The reaction mixture was concentrated,partitioned between water (10 ml) and EtOAc (2×10 ml). The organic layerwas dried over sodium sulfate, filtered, concentrated and columnpurified (CH₂Cl₂: MeOH: methanol-NH₃ (1.0M) (4.5:0.25:0.25) to yield0.0528 g (81%) of the product as a syrup.

Step E.

4-(1H-Imidazol-4-yl-methyl)-isoquinoline dihydrochloride. To4-(1H-Imidazol-4-yl-methyl)-isoquinoline (0.053 g, 0.253 mmol) in 5 mlmethanol, 3 ml of HCl in dioxane was added and the reaction mixture wasconcentrated under reduced pressure to give 0.071 g, (100%) of theproduct as a solid. Anal. Calcd. for C₁₃H_(≦)N₃Cl₂ 1.3 mole H₂O: C,51.10; H, 5.15; N, 13.75. Found: C, 51.27; H, 4.97; N, 13.54.

EXAMPLE 43 1-(1H-Imidazol-4-yl-methyl)-isoquinoline dihydrochloride

Step A.

4-(1H-Imidazol-4-yl-methyl)-isoquinoline. This compound was preparedaccording to experimental conditions outlined in example 42, startingfrom isoquinoline-1-carbaldehyde (F. Minisci et al. J. Org. Chem. 1986,51, 536).

Step B.

1-(1H-Imidazol-4-yl-methyl)-isoquinoline dihydrochloride. To1-(1H-Imidazol-4-yl-methyl)-isoquinoline (0.124 g, 0.592 mmol) in 5 mlmethanol, 3 ml of HCl in dioxane was added and the reaction mixture wasconcentrated under reduced pressure to give 0.127 g, (74%) of theproduct as a pale yellow solid which was recrystallized fromisopropanol-ether: m.p. 240-242° C.; Anal. Calcd. for C₁₃H₁₃N₁C₂: 0.6mole H₂O: C, 53.29; H, 4.89. Found: C, 53.30; H. 5.04.

EXAMPLE 44 4-(1H-Imidazol-4-yl-methyl)-3-methylisocuinolinedihydrochloride

Step A.

4-Bromo-3-methylisoquinoline. To 3-methylisoquinoline (0.500 g, 3.49mmol) in 1 ml nitrobenzene, bromine (0.196 ml, 3.84 mmol) was added andthe contents heated in a sealed tube at 180° C. for 4 hours. Thesolution was cooled to room temperature, neutralized with solid sodiumcarbonate (pH=8) and extracted with ethyl acetate (2×20 ml). The organiclayer was dried over sodium sulfate, filtered, concentrated and columnpurified (hexane:EtOAc; 4.5:0.5) to give 0.560 g (72%) of the product assyrup.

Step B.

3-methylisoquinoline-4-carbaldehyde. To a solution of n-BuLi (2.5M,0.869 ml, 2.17 mmol)) in 10 ml anhydrous THF at −50° C.,4-bromo-3-methylisoquinoline (0.460 q, 2.07 mmol) was added. After 10minutes of stirring, DMF (0.32 g, 4.14 mmol) was added to the solution.The reaction mixture was allowed to stir at −50° C. for 20 minutes andthen at room temperature for 15 minutes. 5 ml of in HCl was added andthe solution was stirred for another 5 minuses. The reaction mixture wasneutralized with saturated solution of NaHCO₃ (25 ml) and partitionedbetween ethylacetate (2×20 ml) and water (10 ml). The organic layer wasdried over sodium sulfate, filtered, concentrated and column purified(hexane:EtOAc; 3:2) to give 0.151 g (43%) of the product as a syrup.

Step C.

4-(1H-Imidazol-4-yl-methyl)-3-methylisoquinoline. This compound wasprepared from 3-methylisoquinoline-4-carbaldehyde employing reactionconditions outlined in example 42. Yield 0.042 g (81%).

Step D.

4-(1H-Imidazol-4-yl-methyl)-3-methylisoquinoline dihydrochloride. To4-(1H-Imidazol-4-yl-methyl)-3-methylisoquinoline (0.042 9, 1.88 mmol) in5 ml methanol, 3 ml of HCl in dioxane was added and the reaction mixturewas concentrated under reduced pressure to give 0.042, (76%) of theproduct as a pale yellow solid which was recrystallized fromisopropanol-ether. m.p. 160-165° C.; Anal. Calcd. for C₁₄H₁₃N₃C₁ ₂ 1.1mole H₂O: C, 53.21; H, 5.49. Found: C, 53.02; H, 5.75.

It is understood that additional compounds may be synthesized under thegeneral synthetic schemes referred to herein using appropriatelysubstituted starting materials.

EXAMPLE 45

As a specific embodiment of an oral composition of a compound of thisinvention, 100 mg of one of the compounds described herein is formulatedwith sufficient finely divided lactose to provide a total amount of 580to 590 mg to fill a size O hard gel capsule.

Pharmacological Profiles of the Compounds at Cloned Human α AdrenergicReceptors

Binding and functional assays were performed using stably transfectedcells expressing human α adrenergic receptors. Equilibrium competitionbinding assays were performed with membrane preparations from culturedLM(tk−) cells stably transfected with the cloned human adrenoceptorsubtypes except for a₂₁, which was expressed In Y-1 cells, using[³H]prazosin for α₁ receptors and [³H]rauwolscine for α₁ receptors.

Protocol for the Determination of the Potency of Ligands

The activity of the compounds at the different receptors was determinedin vitro using cultured cell lines, each selectively expressing only oneα adrenergic receptor subtype (α_(1a), α_(1b), α_(1c), α_(2a), α_(2b),or α_(2c)). These cell lines were prepared by transfecting cloned cDNAor cloned genomic DNA or constructs containing both genomic DNA and cDNAencoding the human a adrenergic receptors as described below.

Human a_(2a) Adrenergic Receptor

The entire coding region of α_(2a) (1350 bp), including 1.0kilobasepairs of 5′ untranslated sequence (5′UT) and 100 bp of 3′untranslated sequence (3′UT), was cloned into the SmaI site of theeukaryotic expression vector pCEXV-3. The insert housing this codingregion was a 2.5 kb Kpnl/HindIII human placenta genomic fragment whichwas end-blunted by either T4 polymerase or Klenow fragment of DNApolymerase. Stable cell lines were obtained by to-transfection with theplasmid pGCcos3neo (plasmid containing the α_(2a) receptor gene) and theplasmid pGCcos3neo (plasmid containing the aminoglycoside transferasegene) into LM(tk−), CHO, and NIH3T3 cells, using calcium phosphatetechnique. The cells were grown in a controlled environment (37° C., 5%CO₂) as monolayers in Dulbecco's modified Eagle's Medium (GIBCO, GrandIsland, N.Y.) containing 25 mM glucose and supplemented with 10% bovinecalf serum, 100 units/mL penicillin g, and 100 mg/mL streptomycinsulfate. Stable clones were then selected for resistance to theantibiotic G-418 (1 mg/mL), and membranes were harvested and assayed fortheir ability to bind [³H]rauwolscine as described below (see“Radioligand Binding Assays”).

Human α_(2b) Adrenergic Receptor

The entire coding region of α_(2b) (1350 bp), including 393 bp of 5′untranslated sequence and 11 bp of 3′ untranslated sequence, was clonedinto the eukaryotic expression vector pcEXV-3. Stable cell lines wereselected as described above.

Human α_(2c) Adrenergic Receptor

The entire coding region of α_(2c) (1383 bp), including 2 bp of 5′ UTand 400 bp of 3′ UT, was cloned into the SmaI site of the eukaryoticexpression vector pCEXV-3. The insert housing this coding region was a1.8 kb Ncol/EcoR₁ human spleen genomic fragment which was end-blunted byeither T₄ polymerase or Klenow fragment of DNA polymerase. Stable celllines were selected as described above.

Stable cell lines expressing the human α₂ adrenergic receptors describedabove as well as stable cell lines expressing the human α₁ adrenergicreceptors have been deposited with the American Type Culture Collection(ATCC), 12301 Parklawn Drive, Rockville, Md., 20852, U.S.A., under theprovisions of the Budapest Treaty for the International Recognition ofthe Deposit of Microorganisms for the Purposes of Patent Procedure. Thecell line expressing the human α_(2a) receptor is designated L-α_(2A)and was deposited on Nov. 6, 1992, under ATCC Accession NumberCRL-11180. The cell line expressing the human α_(2b) receptor isdesignated L-NGC-α_(2B), and was deposited on Oct. 25, 1989 under ATCCAccession Number CRL-10275. The cell line expressing the human α_(2c)receptor is designated L-_(α) _(2c) and was deposited on Nov. 6, 1992,under ATCC Accession Number CRL-11181.

The cell line expressing the human α_(1a) receptor is designatedL-α_(1A) and was deposited on Sep. 25, 1992, under ATCC Accession NumberCRL-11138. The human α_(1a) receptor is now known as the “α_(1d)”receptor due to a nomenclature change by the IUPHAR NomenclatureCommittee, as outlined in the 1995 Receptor and Ion Channel NomenclatureSupplement (Watson and Girdlestone, 1995). The cell line expressing thehuman α_(1c) receptor is designated L-α_(1B) and was deposited on Sep.29, 1992 under ATCC Accession Number CRL-11139. The cell line expressingthe human a receptor is designated L-α_(1B) and was deposited on Sep.25, 1992, under ATCC Accession Number CRL-11140. The human α_(1c)receptor was also renamed by the IUPHAR Nomenclature Committee and isnow known as the “α_(1a)” receptor.

Radioligand Binding Assays

The stable cell lines described above were scraped from culture flasksinto 5 mL of 5 mM Tris-HCl, 5 nM EDTA, pH 7.5, and lysed by sonication.The cell lysates were centrifuged at 1,000 rpm for 5 min. at 4° C., andthe supernatant was centrifuged at 30,000×g for 20 min. at 4° C. Thepellet was suspended in 50 mM Tris-HCl, 1 mM MgCl₂, and 0.1% ascorbicacid at pH 7.5. Binding of the α₂ antagonist [³H]rauwolscine (0.5 nM) orthe α₁ antagonist [³H]prazosin (0.5 nM) to membrane preparations ofLM(tk−) cells was done in a final volume of 0.25 mL and incubated at 37°C. for 20 min. Nonspecific binding was determined in the presence of 10mM phentolamine. The reaction was stopped by filtration through GF/Bfilters using a cell harvester. Inhibition experiments routinelyconsisting of 7 concentrations of the tested compounds were analyzedusing a non-linear regression curve-fitting computer program to obtainKi values.

Measurement of α₂ Agonist Activity

The agonist activity (expressed as pEC₅₀) was measured as a function ofthe ability to inhibit the forskolin-stimulated synthesis of cyclicadenosine monophosphate (cAMP). The stably transfected cells wereincubated in Ham's F10 with 5 mM theophylline, 10 mM HEPES, 17 mMpargyline, and/or appropriate concentrations of forskolin for 20 min. at37° C. in 5% CO₂. The tested compounds were then added to a finalconcentration of 0.001 nM to 1 mM and incubated for an additional 15min. at 37° C. in 5% CO₂. The medium was aspirated and the reaction wasstopped by the addition of 100 mM HCl. To demonstrate competitiveantagonism, a dose-response curve for norepinephrine was obtained inparallel using a fixed dose of norepinephrine (0.32 mM). The plates werestored at 4° C. for 15 min. and assayed to determine the linearconcentration of cAMP. The appropriate dilution was interpolated fromthe standard curve of cold cAMP. The assessment of cAMP formation wasdetermined by radioimmunoassay (cAMP radioimmunoassay kit; Advancedmagnetics, Cambridge, Mass.). Radioactivity was quantified using aPackard COBRA Auto Gamma counter equipped with data reduction software.

Binding affinities were measured for the compounds of the invention atthe six a adrenergic receptor subtypes described above. The compoundswere found to be α₂ selective agonists. The compounds were also found toexhibit weak binding to the α₁ receptors relative to the binding of thecompounds to the α₂ receptors. Table 1 shows the binding and functionalactivities of selected compounds at cloned human α₂ adrenergicreceptors.

TABLE 1 Binding and Functional Activities at Cloned Human α₂Adrenoceptors (IA = Intrinsic Activity). α_(2a) α_(2b) α_(2c) pEC₅₀pEC₅₀ pEC₅₀ Compound pKi (IA) pKi (IA) pKi (IA) Medetomidine 8.62 9.018.63 9.02 8.27 8.83 (1.00) (1.00) (1.00) UK-14, 304 8.15 9.20 7.44 6.757.03 8.23 (1.00) (1.00) (1.00) Example 1 8.94 7.83 8.54 7.44 7.86 7.94(0.48) (0.53) (1.00) Example 21 7.30 6.41 6.78 5.71 6.34 7.79 (0.58)(0.55) (1.00) Example 29 7.83 7.80 7.29 7.04 6.60 7.86 (1.00) (0.40)(1.00) Example 30 7.75 8.53 7.44 6.83 6.51 8.20 (1.00) (0.43) (1.00)Example 36 8.57 5.00 7.39 5.55 7.79 8.14 (0.00) (0.13) (0.77)

What is claimed is:
 1. A compound having the structure:

wherein each R₂ is independently H; F; Cl; Br; I; —NO₂, —CN; straightchained or branched C₁-C₄ alkyl; C₁-C₄ monofluoroalkyl or C₁-C₄polyfluoroalkyl; straight chained or branched C₁-C₄ alkoxy; —OH;—(CH₂)_(q)OH; —COR₄; —CO₂R₄; CONHR₄; phenyl; or benzyl; wherein each R₃is independently H; straight chained or branched C₁-C₄ alkyl; C₂-C₄monofluoroalkyl or C₁-C₄ polyfluoroalkyl; straight chained or branchedC₁-C₄ alkoxy; —(CH₂)_(q)OH; —OH;=N—OR₄; COR₄; CO₂R₄; CONHR₄; phenyl; orbenzyl; wherein each R₄ is independently H; straight chained or branchedC₁-C₄ alkyl, C₁-C₄ monofluoroalkyl or C₁-C₄ polyfluoroalkyl; or phenyl;wherein R₆ is H; straight chained or branched C₁-C₄ alkyl; C₁-C₄monofluoroalkyl or C₁-C₄ polyfluoroalkyl; straight chained or branchedC₁-C₄ alkoxy; —CH₂CH₂(CH₂)_(q)OH; COR₄; CO₂R₄; CONHR₄; phenyl; orbenzyl; wherein R₇ is independently H; —CN; straight chained or branchedC₁-C₄ alkyl; C₁-C₄ monofluoroalkyl or C₁-C₄ polyfluoroalkyl; straightchained or branched C₁-C₄ alkoxy; —OH; —(CH₂)_(q)OH; —COR₄; CO₂R₄;CONHR₄; phenyl; or benzyl; wherein m is 1 or 2; wherein each p isindependently 0, 1 or 2; and wherein each q is independently 0, 1, 2 or3; or a pharmaceutically acceptable salt thereof.
 2. The compound ofclaim 1, wherein the compound is the (+) enantiomer.
 3. The compound ofclaim 1, wherein the compound is the (−) enantiomer.
 4. The compound ofclaim 1 wherein p is at least one and at least one R3 is methyl.
 5. Thecompound of claim 1 wherein p is at least one and at least one R2 ismethyl.
 6. The compound of claim 1 wherein one R2 is bromo.
 7. Apharmaceutical composition comprising a therapeutically effective amountof a compound of claim 1 and a pharmaceutically acceptable carrier.
 8. Amethod for treating an R₂ adrenergic receptor associated disorder in asubject, which comprises administering to the subject an amount of acompound effective to treat the disorder, wherein the compound has thestructure:

wherein each R₂ is independently H; F; Cl; Br; I; —NO₂, —CN; straightchained or branched C₁-C₄ alkyl; C₁-C₄ monofluoroalkyl or C₁-C₄polyfluoroalkyl; straight chained or branched C₁-C₄ alkoxy; —OH;—(CH₂)_(q)OH; —COR₄; CO₂R₄; CONHR₄; phenyl; or benzyl; wherein each R₃is independently H; straight chained or branched C₁-C₄ alkyl; C₁-C₄monofluoroalkyl or C₁-C₄ polyfluoroalkyl; straight chained or branchedC₁-C₄ alkoxy; —(CH₂)_(q)OH; —OH; ═N—OR₄; COR₄; CO₂R₄; CONHR₄; phenyl; orbenzyl; wherein each R₄ is independently H; straight chained or branchedC₁-C₄ alkyl, C₁-C₄ monofluoroalkyl or C₁-C₄ polyfluoroalkyl; or phenyl;wherein R₆ is H; straight chained or branched C₁-C₄ alkyl; C₁-C₄monofluoroalkyl or C₁-C₄ polyfluoroalkyl; straight chained or branchedC₁-C₄ alkoxy; —CH₂CH₂(CH₂)_(q)OH; COR₄; CO₂R₄; CONHR₄; phenyl; orbenzyl; wherein R₇ is independently H; —CN; straight chained or branchedC₁-C₄ alkyl; C₁-C₄ monofluoroalkyl or C₁-C₄ polyfluoroalkyl; straightchained or branched C₁-C₄ alkoxy; —OH; —(CH₂)_(q)OH; —COR₄; CO₂R₄;CONHR₄; phenyl; or benzyl; wherein m is 1 or 2; wherein each p isindependently 0, 1 or 2; and wherein each q is independently 0, 1, 2 or3; or a pharmaceutically acceptable salt thereof.
 9. The method of claim8, wherein the disorder is migraine headache, hypertension or glaucoma.10. A method of treating pain in a subject, which comprisesadministering to the subject an amount of a compound effective to treatthe subject's pain, wherein the compound has the structure:

wherein each R₂ is independently H; F; Cl; Br; I; —NO₂, —CN; straightchained or branched C₁-C₄ alkyl; C₁-C₄ monofluoroalkyl or C₁-C₄polyfluoroalkyl; straight chained or branched C₁-C₄ alkoxy; —OH;—(CH₂)_(q)OH; —COR₄; CO₂R₄; CONHR₄; phenyl; or benzyl; wherein each R₃is independently H; straight chained or branched C₁-C₄ alkyl; C₁-C₄monofluoroalkyl or C₁-C₄ polyfluoroalkyl; straight chained or branchedC₁-C₄ alkoxy; —(CH₂)_(q)OH; —OH; ═N—OR₄; COR₄; CO₂R₄; CONHR₄; phenyl; orbenzyl; wherein each R₄ is independently H; straight chained or branchedC₁-C₄ alkyl, C₁-C₄ monofluoroalkyl or C₁-C₄ polyfluoroalkyl; or phenyl;wherein R₆ is H; straight chained or branched C₁-C₄ alkyl; C₁-C₄monofluoroalkyl or C₁-C₄ polyfluoroalkyl; straight chained or branchedC₁-C₄ alkoxy; —CH₂CH₂(CH₂)_(q)OH; COR₄; CO₂R₄; CONHR₄; phenyl; orbenzyl; wherein R₇ is independently H; —CN; straight chained or branchedC₁-C₄ alkyl; C₂-C₄ monofluoroalkyl or C₁-C₄ polyfluoroalkyl; straightchained or branched C₁-C₄ alkoxy; —OH; —(CH₂)_(q)OH; —COR₄; CO₂R₄;CONHR₄; phenyl; or benzyl; wherein m is 1 or 2; wherein each p isindependently 0, 1 or 2; and wherein each q is independently 0, 1, 2 or3; or a pharmaceutically acceptable salt thereof.
 11. The compound ofclaim 1 wherein the compound has the structure:


12. The compound of claim 1 wherein the compound has the structure: